Inhibition of olig2 activity

ABSTRACT

Described herein are compounds and pharmaceutical compositions containing such compounds, which inhibit the activity of Olig2. Also described herein are methods of using such Olig2 inhibitors, alone and in combination with other compounds, for treating cancer and other diseases. In particular the Olig2 inhibitors may be used to treat glioblastoma.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/553,478, filed Aug. 24, 2017, which is a § 371 U.S. National PhaseEntry of International Application PCT/US2016/019932, filed Feb. 26,2016, which claims the benefit of priority from U.S. ProvisionalApplication 62/126,382, filed Feb. 27, 2015, all of which have beenincorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

Current brain tumor therapeutic agents, which are only able to extendmedian survival of patients by six months, cause significant systemictoxicity. This toxicity results in serious long term morbidity of thefew patients that survive, in terms of cognition, endocrine disorders,and motor effects. Currently brain tumors are essentially incurable witha median survival of fifteen months.

SUMMARY OF THE INVENTION

Described herein are compounds of Formula (I), (II), (IIA), (IIB),(IIC), (IID), (III), (IV), (V) or (VI) (hereinafter “compounds ofFormula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or(VI)”), compositions that include such compounds, and methods of usethereof, for inhibition of Olig2 activity.

In one aspect, described herein is a compound of Formula (I):

wherein:

-   -   A is a bond, O, or N(R₁₀);    -   X, Y, and Z are each independently N, or C(R₇) wherein at least        one of X, Y, and Z are N;    -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl;    -   or two R₁ are taken together to form a substituted or        unsubstituted heterocyclic ring or a substituted or        unsubstituted carbocyclic ring;    -   R₂ and R₃ are each independently H, —CN, C₁-C₄alkyl,        C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ are        taken together to form a 5- or 6-membered heterocyclic ring;    -   R₅ is halogen, —CN, —OH, —CF₃, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   R₆ is substituted or unsubstituted C₂-C₇heterocycloalkyl,        substituted or unsubstituted C₃-C₈cycloalkyl, substituted or        unsubstituted C₂-C₇heteroaryl, —(C(R₁₄)(R₁₅))_(m)R₂₁,        —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), or

-   -   R₁₁ and R₁₂ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or R₁₁ and R₁₂ are taken together to        form a 5-, 6-, 7-, or 8-membered heterocyclic ring;    -   J is C(H), or N;    -   R₁₃ is H, substituted or unsubstituted C₁-C₆alkyl, substituted        or unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        —C₁-C₄alkylC₆-C₁₀aryl, or substituted or unsubstituted        —C₁-C₄alkyC₂-C₇heteroaryl;    -   each R₇ is independently H, halogen, —CN, —OH, —CF₃, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted        or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   each R₁₄ and R₁₅ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or    -   R₁₄ and R₁₅ are taken together to form a 4-, 5-, 6-membered        cycloalkyl ring;    -   R₂₁ is halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,        —SR₂₂, —N(R₂₂)S(═O)₂R₂₃, —S(═O)₂N(R₂₂)₂, —S(═O)R₂₃, —S(═O)₂R₂₃,        —C(═O)R₂₃, —CO₂R₂₂, —C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted        or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   each R₂₂ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₂₃ is substituted or unsubstituted C₁-C₆alkyl;    -   each R₈ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₉ is substituted or unsubstituted C₁-C₆alkyl;    -   R₁₀ is H or unsubstituted C₁-C₄alkyl;    -   m is 2-6;    -   n is 0-5;    -   p is 1-3;    -   q is 1-3; or    -   a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In one embodiment is a compound of Formula (I) wherein R₂ and R₃ areeach independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(I) wherein R₂ and R₃ are each H. In another embodiment is a compound ofFormula (I) wherein R₂ and R₃ are taken together to form a 5- or6-membered heterocyclic ring. In another embodiment is a compound ofFormula (I) wherein R₂ and R₃ are taken together to form a 5-memberedheterocyclic ring. In another embodiment is a compound of Formula (I)wherein R₆ is substituted or unsubstituted C₂-C₇heteroaryl. In a furtherembodiment is a compound of Formula (I) wherein R₆ is substituted orunsubstituted pyridyl. In another embodiment is a compound of Formula(I) wherein R₆ is

In another embodiment is a compound of Formula (I) wherein R₁₃ is H. Inanother embodiment is a compound of Formula (I) wherein R₁₃ issubstituted or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (I) wherein R₁₃ is —CH₃. In another embodiment is acompound of Formula (I) wherein R₁₃ is —CH₂CH₃. In another embodiment isa compound of Formula (I) wherein J is C(H). In another embodiment is acompound of Formula (I) wherein p is 2 and q is 1. In another embodimentis a compound of Formula (I) wherein p is 3 and q is 1. In anotherembodiment is a compound of Formula (I) wherein p is 2 and q is 2. Inanother embodiment of the aforementioned embodiments, is a compound ofFormula (I) wherein J is N. In another embodiment is a compound ofFormula (I) wherein p is 2 and q is 2. In another embodiment of theaforementioned embodiments, is a compound of Formula (I) wherein R₆ issubstituted or unsubstituted C₂-C₇heterocycloalkyl. In anotherembodiment of the aforementioned embodiments, is a compound of Formula(I) wherein R₆ is substituted or unsubstituted morpholinyl. In anotherembodiment of the aforementioned embodiments, is a compound of Formula(I) wherein R₆ is substituted or unsubstituted piperidinyl. In anotherembodiment of the aforementioned embodiments, is a compound of Formula(I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₂₁. In another embodiment of theaforementioned embodiments, is a compound of Formula (I) wherein R₂₁ is—OH. In another embodiment of the aforementioned embodiments, is acompound of Formula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂). Inanother embodiment of the aforementioned embodiments, is a compound ofFormula (I) wherein R₁₁ and R₁₂ are each CH₃. In another embodiment ofthe aforementioned embodiments, is a compound of Formula (I) wherein R₁₄and R₁₅ are each H. In another embodiment of the aforementionedembodiments, is a compound of Formula (I) wherein m is 2. In anotherembodiment of the aforementioned embodiments, is a compound of Formula(I) wherein m is 3. In another embodiment of the aforementionedembodiments, is a compound of Formula (I) wherein A is N(R₁₀). Inanother embodiment is a compound of Formula (I) wherein R₁₀ is H or CH₃.In another embodiment of the aforementioned embodiments, is a compoundof Formula (I) wherein A is O. In another embodiment of theaforementioned embodiments, is a compound of Formula (I) wherein A is abond. In another embodiment of the aforementioned embodiments, is acompound of Formula (I) wherein R₅ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (I) whereinR₅ is CH₃. In another embodiment is a compound of Formula (I) wherein R₅is CH₂CH₃. In another embodiment of the aforementioned embodiments, is acompound of Formula (I) wherein n is 2. In another embodiment of theaforementioned embodiments, is a compound of Formula (I) wherein n is 1.In another embodiment of the aforementioned embodiments, is a compoundof Formula (I) wherein n is 0. In another embodiment of theaforementioned embodiments, is a compound of Formula (I) wherein each R₁is independently halogen, —CN, —NO₂, —OH, —CF₃, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (I) wherein each R₁ is independently halogen, —CN, —OH, —CF₃,substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment of the aforementioned embodiments, isa compound of Formula (I) wherein two R₁ are taken together to form asubstituted or unsubstituted heterocyclic ring or a substituted orunsubstituted carbocyclic ring. In another embodiment of theaforementioned embodiments, is a compound of Formula (I) wherein X isC(R)₇; Y is N; and Z is N. In another embodiment of the aforementionedembodiments, is a compound of Formula (I) wherein X is C(R)₇; Y isC(R)₇; and Z is N. In another embodiment of the aforementionedembodiments, is a compound of Formula (I) wherein X is C(R)₇; Y is N;and Z is C(R)₇. In another embodiment of the aforementioned embodiments,is a compound of Formula (I) wherein X is C(R)₇; Y is C(R)₇; and Z isC(R)₇. In another embodiment of the aforementioned embodiments, is acompound of Formula (I) wherein R₇ is H. In another embodiment of theaforementioned embodiments, is a compound of Formula (I) wherein X is N;Y is N; and Z is N.

In another aspect, described herein is a compound of Formula (II):

wherein:

-   -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl;    -   or two R₁ are taken together to form a substituted or        unsubstituted heterocyclic ring or a substituted or        unsubstituted carbocyclic ring;    -   R₂ and R₃ are each independently H, —CN, C₁-C₄alkyl,        C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ are        taken together to form a 5- or 6-membered heterocyclic ring;    -   R₅ is halogen, —CN, —OH, —CF₃, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   R₆ is substituted or unsubstituted C₂-C₇heterocycloalkyl,        substituted or unsubstituted C₃-C₈cycloalkyl, substituted or        unsubstituted C₂-C₇heteroaryl, —(C(R₁₄)(R₁₅))_(m)R₂₁, or

-   -   J is C(H);    -   R₁₃ is H, substituted or unsubstituted C₁-C₆alkyl, substituted        or unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        —C₁-C₄alkylC₆-C₁₀aryl, or substituted or unsubstituted        —C₁-C₄alkyC₂-C₇heteroaryl;    -   each R₁₄ and R₁₅ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or    -   R₁₄ and R₁₅ are taken together to form a 4-, 5-, 6-membered        cycloalkyl ring;    -   R₂₁ is halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,        —SR₂₂, —N(R₂₂)S(═O)₂R₂₃, —S(═O)₂N(R₂₂)₂, —S(═O)R₂₃, —S(═O)₂R₂₃,        —C(═O)R₂₃, —CO₂R₂₂, —C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substituted        or unsubstituted C₁-C₆alkoxy, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted C₆-C₁₀aryl, or substituted or        unsubstituted C₂-C₇heteroaryl;    -   each R₂₂ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₂₃ is substituted or unsubstituted C₁-C₆alkyl;    -   each R₈ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₉ is substituted or unsubstituted C₁-C₆alkyl;    -   R₁₀ is H or unsubstituted C₁-C₄alkyl;    -   m is 2-6;    -   n is 0-5;    -   p is 1-3;    -   q is 1-3; or    -   a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In one embodiment is a compound of Formula (II) wherein R₂ and R₃ areeach independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(II) wherein R₂ and R₃ are each H. In another embodiment is a compoundof Formula (II) wherein R₂ and R₃ are taken together to form a 5- or6-membered heterocyclic ring. In another embodiment is a compound ofFormula (II) wherein R₂ and R₃ are taken together to form a 5-memberedheterocyclic ring. In another embodiment of the aforementionedembodiments, is a compound of Formula (II) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁. In another embodiment of the aforementionedembodiments, is a compound of Formula (II) wherein R₂₁ is —OH,—N(R₂₂)S(═O)₂R₂₃, —CO₂R₂₂, —C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substitutedor unsubstituted C₁-C₆alkoxy, or substituted or unsubstitutedC₂-C₇heteroaryl. In another embodiment of the aforementionedembodiments, is a compound of Formula (II) wherein R₂₁ is —OH. Inanother embodiment of the aforementioned embodiments, is a compound ofFormula (II) wherein R₂₁ is —N(R₂₂)S(═O)₂R₂₃. In another embodiment ofthe aforementioned embodiments, is a compound of Formula (II) whereinR₂₁ is —N(R₂₂)C(═O)R₂₃. In a further embodiment, is a compound ofFormula (II) wherein R₂₁ is —N(R₂₂)S(═O)₂R₂₃. In another embodiment ofthe aforementioned embodiments, is a compound of Formula (II) whereinR₂₁ is substituted or unsubstituted C₁-C₆alkoxy. In another embodimentof the aforementioned embodiments, is a compound of Formula (II) whereinR₂₁ is substituted or unsubstituted C₂-C₇heteroaryl. In anotherembodiment of the aforementioned embodiments, is a compound of Formula(II) wherein each R₂₂ is independently H or unsubstituted C₁-C₆alkyl;and R₂₃ is unsubstituted C₁-C₆alkyl. In another embodiment of theaforementioned embodiments, is a compound of Formula (II) wherein R₁₄and R₁₅ are each independently H or substituted or unsubstitutedC₁-C₆alkyl. In another embodiment of the aforementioned embodiments, isa compound of Formula (II) wherein R₁₄ and R₁₅ are each H. In anotherembodiment of the aforementioned embodiments, is a compound of Formula(II) wherein m is 2. In another embodiment of the aforementionedembodiments, is a compound of Formula (II) wherein m is 3. In anotherembodiment is a compound of Formula (II) wherein R₆ is substituted orunsubstituted C₂-C₇heteroaryl. In a further embodiment is a compound ofFormula (II) wherein R₆ is substituted or unsubstituted pyridyl. Inanother embodiment of the aforementioned embodiments, is a compound ofFormula (II) wherein R₆ is substituted or unsubstitutedC₂-C₇heterocycloalkyl. In another embodiment of the aforementionedembodiments, is a compound of Formula (II) wherein R₆ is substituted orunsubstituted morpholinyl. In another embodiment of the aforementionedembodiments, is a compound of Formula (II) wherein R₆ is substituted orunsubstituted piperidinyl. In another embodiment is a compound ofFormula (II) wherein R₁₀ is H or CH₃.

In another aspect, described herein is a compound of Formula (IIA):

wherein:

-   -   wherein:    -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl;    -   or two R₁ are taken together to form a substituted or        unsubstituted heterocyclic ring or a substituted or        unsubstituted carbocyclic ring;    -   R₂ and R₃ are each independently H, —CN, C₁-C₄alkyl,        C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ are        taken together to form a 5- or 6-membered heterocyclic ring;    -   R₄ is H, halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —SR₈,        —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉, —C(═O)R₉,        —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted        or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl; or        two R₁ are taken together to form a substituted or unsubstituted        heterocyclic ring or a substituted or unsubstituted carbocyclic        ring; wherein when n is 0, R₄ is not halogen;    -   R₅ is halogen, —CN, —OH, —CF₃, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂);    -   R₁₁ and R₁₂ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or R₁₁ and R₁₂ are taken together to        form a 5-, 6-, 7-, or 8-membered heterocyclic ring;    -   R₁₃ is H, substituted or unsubstituted C₁-C₆alkyl, substituted        or unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        —C₁-C₄alkylC₆-C₁₀aryl, or substituted or unsubstituted        —C₁-C₄alkyC₂-C₇heteroaryl;    -   each R₁₄ and R₁₅ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or    -   R₁₄ and R₁₅ are taken together to form a 4-, 5-, 6-membered        cycloalkyl ring;    -   each R₈ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₉ is substituted or unsubstituted C₁-C₆alkyl;    -   R₁₀ is H, or C₁-C₄alkyl;    -   m is 2-6;    -   n is 0-4; or    -   a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In one embodiment is a compound of Formula (IIA) wherein R₂ and R₃ areeach independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(IIA) wherein R₂ and R₃ are each H. In another embodiment is a compoundof Formula (IIA) wherein R₂ and R₃ are taken together to form a 5- or6-membered heterocyclic ring. In another embodiment is a compound ofFormula (IIA) wherein R₂ and R₃ are taken together to form a 5-memberedheterocyclic ring. In another embodiment of the aforementionedembodiments, is a compound of Formula (II) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₄ and R₁₅ are each H. In anotherembodiment of the aforementioned embodiments, is a compound of Formula(II) wherein R₁₁ and R₁₂ are each independently H, or substituted orunsubstituted C₁-C₆alkyl. In another embodiment of the aforementionedembodiments, is a compound of Formula (II) wherein R₁₁ and R₁₂ are eachindependently unsubstituted C₁-C₆alkyl. In another embodiment of theaforementioned embodiments, is a compound of Formula (II) wherein R₁₁and R₁₂ are each —CH₃. In another embodiment of the aforementionedembodiments, is a compound of Formula (II) wherein m is 2. In anotherembodiment of the aforementioned embodiments, is a compound of Formula(II) wherein m is 3. In another embodiment is a compound of Formula (II)wherein R₁₀ is H or CH₃. In another embodiment of the aforementionedembodiments, is a compound of Formula (II) wherein n is 0. In anotherembodiment of the aforementioned embodiments, is a compound of Formula(II) wherein n is 1.

In another aspect, described herein is a compound of Formula (VI):

wherein:

-   -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl;    -   or two R₁ are taken together to form a substituted or        unsubstituted heterocyclic ring or a substituted or        unsubstituted carbocyclic ring;    -   R₂ and R₃ are each independently H or C₁-C₄alkyl; or R₂ and R₃        are taken together to form a 5- or 6-membered heterocyclic ring;    -   R₅ is substituted or unsubstituted C₁-C₆alkyl;    -   R₆ is unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₂-C₇heteroaryl,        —(C(R₁₄)(R₅))_(m)R₂₁,

-   -   J is C(H);    -   R₁₃ is H, substituted or unsubstituted C₁-C₆alkyl, substituted        or unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        —C₁-C₄alkylC₆-C₁₀aryl, or substituted or unsubstituted        —C₁-C₄alkyC₂-C₇heteroaryl;    -   each R₁₄ and R₁₅ are each independently H, halogen, or        substituted or unsubstituted C₁-C₆alkyl;    -   R₂₁ is halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,        —SR₂₂, —N(R₂₂)S(═O)₂R₂₃, —S(═O)₂N(R₂₂)₂, —S(═O)R₂₃, —S(═O)₂R₂₃,        —C(═O)R₂₃, —CO₂R₂₂, —C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substituted        or unsubstituted C₁-C₆alkoxy, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, or substituted or unsubstituted        C₂-C₇heteroaryl;    -   each R₂₂ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₂₃ is substituted or unsubstituted C₁-C₆alkyl;    -   each R₈ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₉ is substituted or unsubstituted C₁-C₆alkyl;    -   R₁₀ is H;    -   m is 2-6;    -   n is 0-5;    -   p is 1-3;    -   q is 1-3; or    -   a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments is a compound of Formula (VI) wherein R₂ and R₃ areeach independently H or C₁-C₄alkyl. In another embodiment is a compoundof Formula (VI) wherein R₂ and R₃ are each H. In another embodiment is acompound of Formula (VI) wherein R₂ and R₃ are taken together to form a5- or 6-membered heterocyclic ring. In another embodiment is a compoundof Formula (VI) wherein R₂ and R₃ are taken together to form a5-membered heterocyclic ring. In another embodiment is a compound ofFormula (VI) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₂₁. In another embodimentis a compound of Formula (VI) wherein R₁₄ and R₁₅ are each independentlyH, halogen, or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (VI) wherein R₁₄ and R₁₅ are each H. In anotherembodiment is a compound of Formula (VI) wherein R₂₁ is —OH,—N(R₂₂)S(═O)₂R₂₃, —CO₂R₂₂, —C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substitutedor unsubstituted C₁-C₆alkoxy, or substituted or unsubstitutedC₂-C₇heteroaryl. In another embodiment of the aforementionedembodiments, is a compound of Formula (VI) wherein R₂₁ is —OH. Inanother embodiment of the aforementioned embodiments, is a compound ofFormula (VI) wherein R₂₁ is —N(R₂₂)S(═O)₂R₂₃. In another embodiment ofthe aforementioned embodiments, is a compound of Formula (VI) whereinR₂₁ is —N(R₂₂)C(═O)R₂₃. In a further embodiment, R₂₁ is—N(R₂₂)S(═O)₂R₂₃. In another embodiment of the aforementionedembodiments, is a compound of Formula (VI) wherein R₂₁ is substituted orunsubstituted C₁-C₆alkoxy. In another embodiment of the aforementionedembodiments, is a compound of Formula (VI) wherein R₂₁ is substituted orunsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (VI) wherein each R₂₂ is independently H or unsubstitutedC₁-C₆alkyl; and R₂₃ is unsubstituted C₁-C₆alkyl. In another embodimentis a compound of Formula (VI) wherein m is 2. In another embodiment is acompound of Formula (VI) wherein m is 3. In another embodiment is acompound of Formula (VI) wherein R₆ is

In another embodiment is a compound of Formula (VI) wherein R₆ is

In another embodiment is a compound of Formula (VI) wherein R₁₃ is H orunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(VI) wherein each R₁ is independently halogen, —OCF₃, —CF₃,unsubstituted C₁-C₆alkyl, or unsubstituted C₁-C₆alkoxy. In anotherembodiment is a compound of Formula (VI) wherein each R₁ isindependently halogen. In another embodiment is a compound of Formula(VI) wherein n is 1. In another embodiment is a compound of Formula (VI)wherein each R₁ is independently halogen. In another embodiment is acompound of Formula (VI) wherein n is 2. In another embodiment is acompound of Formula (VI) wherein each R₁ is independently halogen. Inanother embodiment is a compound of Formula (VI) wherein n is 0.

In another aspect is a pharmaceutical composition comprising a compoundof Formula (I), (II), or (IIA) or a pharmaceutically acceptable salt,solvate, or prodrug thereof, and at least one pharmaceuticallyacceptable excipient. In another aspect is a pharmaceutical compositioncomprising a compound of Formula (I), (II), (IIA), or (VI) or apharmaceutically acceptable salt, solvate, or prodrug thereof, and atleast one pharmaceutically acceptable excipient.

In another aspect is the use of a compound of Formula (I), (II), or(IIA) or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof, for theformulation of a medicament for inhibiting the activity of Olig2 in acell is provided. The method includes contacting the cell with acompound of Formula (I), (II), or (IIA) including embodiments thereof.

In another aspect is the use of a compound of Formula (I), (II), (IIA),or (VI) or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or pharmaceutically acceptable prodrug thereof, forthe formulation of a medicament for inhibiting the activity of Olig2 ina cell is provided. The method includes contacting the cell with acompound of Formula (I), (II), (IIA), or (VI) including embodimentsthereof.

In a further aspect is a method of treating a disease, disorder orcondition in a subject that would benefit from inhibition of Olig2activity comprising administering to the subject in need thereof acomposition comprising a compound of Formula (I), (II), or (IIA) or apharmaceutically acceptable salt, solvate, or prodrug thereof. In someembodiments is a method of treating a disease, disorder or condition ina subject that would benefit from inhibition of Olig2 activitycomprising administering to the subject in need thereof a compositioncomprising a compound of Formula (I), (II), or (IIA) or apharmaceutically acceptable salt, solvate, or prodrug thereof, whereinthe disease is cancer or Down's Syndrome.

In a further aspect is a method of treating a disease, disorder orcondition in a subject that would benefit from inhibition of Olig2activity comprising administering to the subject in need thereof acomposition comprising a compound of Formula (I), (II), (IIA), or (VI)or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Insome embodiments is a method of treating a disease, disorder orcondition in a subject that would benefit from inhibition of Olig2activity comprising administering to the subject in need thereof acomposition comprising a compound of Formula (I), (II), (IIA), or (VI)or a pharmaceutically acceptable salt, solvate, or prodrug thereof,wherein the disease is cancer or Down's Syndrome.

In another aspect is a method for treating a disease in a subjectcomprising administering to the subject in need thereof a compositioncomprising a compound of Formula (I), (II), or (IIA), or apharmaceutically acceptable salt, solvate, or prodrug thereof, whereinthe disease is cancer or Down's Syndrome. In some embodiments is amethod for treating cancer in a subject comprising administering to thesubject in need thereof a composition comprising a compound of Formula(I), (II), or (IIA) or a pharmaceutically acceptable salt, solvate, orprodrug thereof. In some embodiments is a method for treating Down'sSyndrome in a subject comprising administering to the subject in needthereof a composition comprising a compound of Formula (I), (II), or(IIA) or a pharmaceutically acceptable salt, solvate, or prodrugthereof.

In another aspect is a method for treating a disease in a subjectcomprising administering to the subject in need thereof a compositioncomprising a compound of Formula (I), (II), (IIA), or (VI) or apharmaceutically acceptable salt, solvate, or prodrug thereof; whereinthe disease is cancer or Down's Syndrome. In some embodiments is amethod for treating cancer in a subject comprising administering to thesubject in need thereof a composition comprising a compound of Formula(I), (II), or (IIA) or a pharmaceutically acceptable salt, solvate, orprodrug thereof. In some embodiments is a method for treating Down'sSyndrome in a subject comprising administering to the subject in needthereof a composition comprising a compound of Formula (I), (II), (IIA),or (VI) or a pharmaceutically acceptable salt, solvate, or prodrugthereof.

In another embodiment is a method for treating cancer in a subjectcomprising administering to the subject in need thereof a compositioncomprising a compound of Formula (I), (II), or (IIA) or apharmaceutically acceptable salt, solvate, or prodrug thereof, whereinthe cancer is brain cancer, glioblastoma multiforme, medulloblastoma,astrocytomas, brain stem gliomas, meningiomas, oligodendrogliomas,melanoma, lung cancer, breast cancer, or leukemia. In another embodimentis a method for treating cancer in a subject comprising administering tothe subject in need thereof a composition comprising a compound ofFormula (I), (II), (IIA), or (VI) or a pharmaceutically acceptable salt,solvate, or prodrug thereof, wherein the cancer is brain cancer,glioblastoma multiforme, medulloblastoma, astrocytomas, brain stemgliomas, meningiomas, oligodendrogliomas, melanoma, lung cancer, breastcancer, or leukemia.

In another aspect is a method of inhibiting the activity of Olig2 in acell comprising contacting the cell with a compound of Formula (I),(II), or (IIA) or a pharmaceutically acceptable salt, solvate, orprodrug thereof. In another aspect is a method of inhibiting theactivity of Olig2 in a cell comprising contacting the cell with acompound of Formula (I), (II), (IIA), or (VI) or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof.

In another aspect is the use of a compound of Formula (I), (II), or(IIA) in the manufacture of a medicament for the treatment of a disease,disorder, or condition that would benefit from inhibition of Olig2activity. In another aspect is the use of a compound of Formula (I),(II), (IIA), or (VI) in the manufacture of a medicament for thetreatment of a disease, disorder, or condition that would benefit frominhibition of Olig2 activity.

Other objects, features and advantages of the compounds, compositions,methods, and uses described herein will become apparent from thefollowing detailed description. It should be understood, however, thatthe detailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of thedisclosure will become apparent from this detailed description.

DETAILED DESCRIPTION

The compounds described herein are modulators or inhibitors of theneural and GBM (glioblastoma multiforme) stem cell transcriptionalrepressor OLIG2 (e.g. NM_005806, NP_005797 for human). OLIG2 (alsowritten herein as Olig2) is the oligodendrocyte transcription factor 2.This protein is a member of the bHLH (basic helix-loop-helix) family.The bHLH family is a family of transcription factors that contain thestructure motif characterized by two alpha helices connected by a loop.The transcription factors containing bLHL domains are generally dimeric.Generally one of the helices contains basic amino acid residues thatfacilitate binding to DNA. OLIG2 is normally restricted to the centralnervous system (CNS) in non-disease states, where it is an essentialregulator of progenitor cell fate. OLIG2 homodimerizes andheterodimerizes with the E12 or E47 proteins to then bind and repressthe p21 gene promoter among other effects. P21 is a stem cell and tumorsuppressor, and is directly repressed by OLIG2. P21 is activated by thetumor suppressor p53. p53 occurs in the intact, wild type form in nearly70% of primary GBM patient samples. OLIG2 is highly expressed in alldiffuse gliomas, and is found in virtually 100% of GBM cells positivefor the CD133 stem cell marker. Importantly, OLIG2 is typically notfound in normal brain and in tissues outside the CNS unless they aremalignant, such as T-cell leukemia, melanoma, lung and breast cancer. Noother neural or glial marker gene, and no other transcriptionalrepressor displays as consistent a link to brain cancers. In contrast,membrane receptors (EGFR, PDGFR, etc) are not uniformly expressed amongpatients, and various approaches to targeting them has been met withlimited success in GBM treatment.

The expression of Olig2 in diffuse gliomas likely results from thetransformed stem cell origin of these tumors. It has been found that asmall cohort of the cells present in patient GBM expresses neural stemcell markers including CD133 and nestin, among others. The CD133(+)cells isolated from existing GBM are highly tumorigenic whenorthotopically implanted into mice. In one study, as few as 100 of theCD133(+) cells extracted from a patient GBM produced an invasive tumorwhen transplanted into the brain of a recipient mouse, while 100,000CD133(−) GBM cells were unable to generate a tumor. Consistent withthese findings, a strikingly high percentage of GBM occur in closeproximity to the neural stem cell germinal zones in the brain, i.e.,neural stem cells undergo malignant transformation and migrate somedistance from the germinal zones and establish a GBM.

Another significant finding with respect to GBM cancer stem cells (CSCs)is that the CD133(+) cells are significantly more resistant to radiationand cytotoxic agents used to treat GBM than the bulk of the tumor masswhich is comprised of CD133(−) cells. This suggests that conventionalradio/chemotherapy spares the CSCs within a GBM, and unless these cellsare targeted, the tumor invariably is resurgent, with lethal effect.Moreover, the very few patients that survive GBM suffer lifelongmorbidity from chemo- and radio-toxicity, in terms of cognition,endocrine balance, and other functions.

Olig2 is highly expressed in GBM CSCs, but is only expressed in lowlevels by normal brain and is not detected in tissues outside thenervous system. Olig2 inhibitors would offer a therapeutic marginsuperior to conventional chemotherapy. Low systemic toxicity would bemuch more compatible with long-term clinical management of GBM than isthe case with currently used treatment approaches.

High rates of mortality for patients with brain cancers make thisdisease a leading cause of cancer related death in men, women andchildren. Primary brain tumors are actually the most common solid tumorof childhood and the second leading cause of cancer death afterleukemia. The toxicity of current treatments causes serious life-longmorbidity in the few patients that survive. The development of smallmolecule, orally available drugs with low toxicity effective in braincancers would represent a significant advance. Moreover, the compoundsmay also be effective in other cancers that are stem cell driven andwhich highly express Olig2. These cancers include T-cell leukemias, skincancers, small cell lung cancers, and breast cancers. Moreover, thesecancers often metastasize to the brain. This would be relevant tomillions of patients worldwide.

In some embodiments described herein, are small molecules that inhibitOlig2 which is a transcription factor critical for survival andproliferation of glioblastoma and other brain cancers, i.e.,medulloblastoma, astrocytomas, brain stem gliomas, meningiomas, andoligodendrogliomas. Olig2 especially is detected primarily in the brain,generally not outside the nervous system, and it is highly expressed inglioblastoma tumors. This means that Olig2 inhibition should haverelatively low toxicity to a patient. Olig2 is also over-expressed inmelanomas, lung cancers, breast cancer and T-cell leukemias, so an Olig2inhibitor may also be applicable to the treatment of these cancers.

No other transcription factor or marker displays as consistent a link tobrain cancer as does Olig2, so Olig2 inhibition should compare favorablyto other signaling pathway inhibitors in glioblastoma. Olig2 is a robusttarget in that the hinge region of its dimerization loop is uniquecompared to other proteins of its class (basic helix-loop-helixproteins).

The Olig2 targeted inhibitors described herein should prove unique interms of efficacy and toxicity.

The existing agents, therapeutics, and methods used to treat braincancers include Temozolomide (TMZ—Temodar), radiation, cyclophosphamide,carmustine, carboplatin, and occasional supplementation with Avastin.All these are only somewhat effective standard brain cancer therapeuticagents, and they are very toxic. No brain cancer stem cell inhibitorscurrently exist for brain tumors.

In another aspect, methods of inhibiting the activity of OLIG2 areprovided. The methods include contacting an Olig2 protein with aneffective amount of a compound provided herein (e.g., a compound ofFormula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI).The compound may have the structure of the Formulae provided herein (orany of the embodiments thereof described above). In some embodiments,the methods of inhibiting a Olig2 protein are conducted within a cell.Thus, in certain embodiments, methods of inhibiting the activity ofOlig2 within a cell are provided. The method includes contacting a cellwith an effective amount of a compound provided herein. The compound mayhave the structure of the Formulae provided herein (or any of theembodiments thereof described above). In some embodiments, the cell is aprokaryote or eukaryote. The cell may be a eukaryote (e.g. protozoancell, fungal cell, plant cell or an animal cell). In some embodiments,the cell is a mammalian cell such as a human cell, cow cell, pig cell,horse cell, dog cell and cat cell, mouse cell, or rat cell. In someembodiments, the cell is a human cell. The cell may form part of anorgan or an organism. In certain embodiments, the cell does not formpart of an organ or an organism.

In another aspect, a method of inhibiting the activity of Olig2 in acell is provided. The method includes contacting the cell with acompound as provided herein (e.g. Formula (I), (II), (IIA), (IIB),(IIC), (IID), (III), (IV), and (V)). In some embodiments the compoundbinds the hinge region of the dimerization loop of Olig2. In someembodiments, the compound inhibits dimerization of Olig2.

Compounds

Compounds described herein inhibit the activity of Olig2 within a celland may be used in the treatment of diseases or conditions whereinhibition of Olig2 activity has a beneficial effect.

In one aspect, described herein is a compound of Formula (I):

wherein:

-   -   A is a bond, O, or N(R₁₀);    -   X, Y, and Z are each independently N, or C(R₇) wherein at least        one of X, Y, and Z are N;    -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl;    -   or two R₁ are taken together to form a substituted or        unsubstituted heterocyclic ring or a substituted or        unsubstituted carbocyclic ring;    -   R₂ and R₃ are each independently H, —CN, C₁-C₄alkyl,        C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ are        taken together to form a 5- or 6-membered heterocyclic ring;    -   R₅ is halogen, —CN, —OH, —CF₃, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   R₆ is substituted or unsubstituted C₂-C₇heterocycloalkyl,        substituted or unsubstituted C₃-C₈cycloalkyl, substituted or        unsubstituted C₂-C₇heteroaryl, —(C(R₁₄)(R₁₅))_(m)R₂₁,        —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), or

-   -   R₁₁ and R₁₂ are each independently H, or substituted or        unsubstituted C₁-C₆ alkyl; or R₁₁ and R₁₂ are taken together to        form a 5-, 6-, 7-, or 8-membered heterocyclic ring;    -   J is C(H), or N;    -   R₁₃ is H, substituted or unsubstituted C₁-C₆alkyl, substituted        or unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        —C₁-C₄alkylC₆-C₁₀aryl, or substituted or unsubstituted        —C₁-C₄alkyC₂-C₇heteroaryl;    -   each R₇ is independently H, halogen, —CN, —OH, —CF₃, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted        or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   each R₁₄ and R₁₅ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or    -   R₁₄ and R₁₅ are taken together to form a 4-, 5-, 6-membered        cycloalkyl ring;    -   R₂₁ is halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,        —SR₂₂, —N(R₂₂)S(═O)₂R₂₃, —S(═O)₂N(R₂₂)₂, —S(═O)R₂₃, —S(═O)₂R₂₃,        —C(═O)R₂₃, —CO₂R₂₂, —C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substituted        or unsubstituted C₁-C₆alkoxy, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl;    -   each R₂₂ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₂₃ is substituted or unsubstituted C₁-C₆alkyl;    -   each R₈ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₉ is substituted or unsubstituted C₁-C₆alkyl;    -   R₁₀ is H or unsubstituted C₁-C₄alkyl;    -   m is 2-6;    -   n is 0-5;    -   p is 1-3;    -   q is 1-3; or    -   a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In one embodiment is a compound of Formula (I) wherein A is O or N(R₁₀).In another embodiment is a compound of Formula (I) wherein A is O orN(H). In another embodiment is a compound of Formula (I) wherein A is O.In another embodiment is a compound of Formula (I) wherein A is N(R₁₀).In another embodiment is a compound of Formula (I) wherein A is N(H). Inanother embodiment is a compound of Formula (I) wherein A is N(CH₃). Inanother embodiment is a compound of Formula (I) wherein A is a bond.

In another embodiment is a compound of Formula (I) wherein R₆ issubstituted or unsubstituted C₃-C₈cycloalkyl. In another embodiment is acompound of Formula (I) wherein R₆ is substituted or unsubstitutedcyclopropyl. In another embodiment is a compound of Formula (I) whereinR₆ is substituted or unsubstituted cyclobutyl. In another embodiment isa compound of Formula (I) wherein R₆ is substituted or unsubstitutedcyclopentyl. In another embodiment is a compound of Formula (I) whereinR₆ is substituted or unsubstituted cyclohexyl.

In another embodiment is a compound of Formula (I) wherein R₆ issubstituted or unsubstituted C₂-C₇heteroaryl. In another embodiment is acompound of Formula (I) wherein R₆ is substituted or unsubstitutedfuranyl, thiophenyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl,isoxazolyl, isothiazolyl, pyrazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, indolyl,benzothiophenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, pyrazolopyridinyl,imidazopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, indolizinyl,purinyl, furopyridinyl, thienopyridinyl, furopyrrolyl, furofuranyl,thienofuranyl, 1,4-dihydropyrrolopyrrolyl, thienopyrrolyl,thienothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl,furopyrazolyl, thienopyrazolyl, selenophenyl, selenazolyl, andbenzoisoxazolyl. In another embodiment is a compound of Formula (I)wherein R₆ is substituted or unsubstituted pyridyl. In anotherembodiment is a compound of Formula (I) wherein R₆ is substitutedpyridyl. In another embodiment is a compound of Formula (I) wherein R₆is unsubstituted pyridyl.

In another embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁. In another embodiment is a compound of Formula(I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₂₁, and each R₁₄ and R₁₅ are H. Inanother embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁, m is 2, and each R₁₄ and R₁₅ are H. In anotherembodiment is a compound of Formula (I) wherein R₆ is —(CH₂)_(m)R₂₁, mis 2, and R₂₁ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (I) wherein R₆ is—(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted or unsubstitutedC₃-C₈cycloalkyl. In another embodiment is a compound of Formula (I)wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted orunsubstituted C₆-C₁₀aryl. In another embodiment is a compound of Formula(I) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted orunsubstituted phenyl. In another embodiment is a compound of Formula (I)wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted orunsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (I) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is —OH.

In another embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁, m is 3, and each R₁₄ and R₁₅ are H. In anotherembodiment is a compound of Formula (I) wherein R₆ is —(CH₂)_(m)R₂₁, mis 3, and R₂₁ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (I) wherein R₆ is—(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted or unsubstitutedC₃-C₈cycloalkyl. In another embodiment is a compound of Formula (I)wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted orunsubstituted C₆-C₁₀aryl. In another embodiment is a compound of Formula(I) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted orunsubstituted phenyl. In another embodiment is a compound of Formula (I)wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted orunsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (I) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is —OH.

In another embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂). In another embodiment is a compound ofFormula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), m is 2, andeach R₁₄ and R₁₅ are H. In another embodiment is a compound of Formula(I) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ areeach H. In another embodiment is a compound of Formula (I) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is H. In another embodiment is a compound of Formula(I) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is CH₃, and R₁₂ isH. In another embodiment is a compound of Formula (I) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is substituted or unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (I) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is CH₃, and R₁₂ is CH₃. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ are taken together toform a 5-, 6-, 7-, or 8-membered heterocyclic ring. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ are taken together toform a 5-membered heterocyclic ring. In another embodiment is a compoundof Formula (I) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ andR₁₂ are taken together to form a 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (I) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂). In another embodiment is a compound ofFormula (I) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), m is 3, andeach R₁₄ and R₁₅ are H. In another embodiment is a compound of Formula(I) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ areeach H. In another embodiment is a compound of Formula (I) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is H. In another embodiment is a compound of Formula(I) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is CH₃, and R₁₂ isH. In another embodiment is a compound of Formula (I) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is substituted or unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (I) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is CH₃, and R₁₂ is CH₃. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ are taken together toform a 5-, 6-, 7-, or 8-membered heterocyclic ring. In anotherembodiment is a compound of Formula (I) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ are taken together toform a 5-membered heterocyclic ring. In another embodiment is a compoundof Formula (I) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ andR₁₂ are taken together to form a 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (I) wherein R₆ issubstituted or unsubstituted C₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (I) wherein R₆ is

In another embodiment is a compound of Formula (I) wherein R₆ is

and J is C(H). In another embodiment is a compound of Formula (I)wherein R₆ is

J is C(H), p is 1, and q is 1. In another embodiment is a compound ofFormula (I) wherein R₆ is

J is C(H), p is 2, and q is 1. In another embodiment is a compound ofFormula (I) wherein R₆ is

J is C(H), p is 3, and q is 1. In another embodiment is a compound ofFormula (I) wherein R₆ is

J is C(H), p is 2, and q is 2. In another embodiment is a compound ofFormula (I) wherein R₆ is

J is C(H), p is 1, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (I) whereinR₆ is

J is C(H), p is 2, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (I) whereinR₆ is

J is C(H), p is 3, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (I) whereinR₆ is

J is C(H), p is 2, q is 2, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl.

In another embodiment is a compound of Formula (I) wherein R₆ is

and J is N. In another embodiment is a compound of Formula (I) whereinR₆ is

J is N, p is 2, and q is 2. In another embodiment is a compound ofFormula (I) wherein R₆ is

J is N, p is 2, q is 2, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl.

In another embodiment is a compound of Formula (I) wherein R₅ ishalogen. In another embodiment is a compound of Formula (I) wherein R₅is —CF₃. In another embodiment is a compound of Formula (I) wherein R₅is substituted or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (I) wherein R₅ is —CH₃. In another embodiment is acompound of Formula (I) wherein R₅ is —CH₂CH₃. In another embodiment isa compound of Formula (I) wherein R₅ is substituted or unsubstitutedC₁-C₆heteroalkyl. In another embodiment is a compound of Formula (I)wherein R₅ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (I) wherein R₅ issubstituted or unsubstituted C₃-C₈cycloalkyl. In another embodiment is acompound of Formula (I) wherein R₅ is substituted or unsubstitutedC₆-C₁₀aryl. In another embodiment is a compound of Formula (I) whereinR₅ is substituted or unsubstituted C₂-C₇heteroaryl.

In another embodiment is a compound of Formula (I) wherein R₂ and R₃ areeach independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(I) wherein R₂ and R₃ are each H.

In another embodiment is a compound of Formula (I) wherein R₂ and R₃ areeach independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl; and at least one of R₂ and R₃ is not H. Inanother embodiment is a compound of Formula (I) wherein R₂ is H, and R₃is C₁-C₄alkyl. In another embodiment is a compound of Formula (I)wherein R₂ is H, and R₃ is CH₃. In another embodiment is a compound ofFormula (I) wherein R₂ is H, and R₃ is C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (I) wherein R₂ is H, and R₃ iscyclopropyl. In another embodiment is a compound of Formula (I) whereinR₂ is H, and R₃ is cyclopentyl. In another embodiment is a compound ofFormula (I) wherein R₂ is CH₃, and R₃ is CH₃. In another embodiment is acompound of Formula (I) wherein R₂ is C₁-C₄alkyl, and R₃ is H. Inanother embodiment is a compound of Formula (I) wherein R₂ is CH₃, andR₃ is H. In another embodiment is a compound of Formula (I) wherein R₂is C₃-C₆cycloalkyl, and R₃ is H. In another embodiment is a compound ofFormula (I) wherein R₂ is cyclopropyl, and R₃ is H. In anotherembodiment is a compound of Formula (I) wherein R₂ is cyclopentyl, andR₃ is H.

In another embodiment is a compound of Formula (I) wherein R₂ and R₃ aretaken together to form a 5- or 6-membered heterocyclic ring. In anotherembodiment is a compound of Formula (I) wherein R₂ and R₃ are takentogether to form a 5-membered heterocyclic ring. In another embodimentis a compound of Formula (I) wherein R₂ and R₃ are taken together toform 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (I) wherein n is 0.

In another embodiment is a compound of Formula (I) wherein each R₁ isindependently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,—SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉, —C(═O)R₉,—CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (I) wherein each R₁ is independently halogen, —CN, —OH, —CF₃,substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment is a compound of Formula (I) whereineach R₁ is independently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl, substitutedor unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (I) wherein each R₁ is independently halogen, —CN, —OCF₃,—OCH₂F, —OCF₂H, —CF₃, substituted or unsubstituted C₁-C₆alkyl, orsubstituted or unsubstituted C₁-C₆alkoxy. In another embodiment is acompound of Formula (I) wherein each R₁ is independently halogen, —CN,—OCF₃, —OCH₂F, —OCF₂H, —CF₃, substituted or unsubstituted C₁-C₆alkyl, orsubstituted or unsubstituted C₁-C₆alkoxy, and n is 3. In anotherembodiment is a compound of Formula (I) wherein each R₁ is independentlyhalogen, —CN, —OCF₃, —OCH₂F, —OCF₂H, —CF₃, substituted or unsubstitutedC₁-C₆alkyl, or substituted or unsubstituted C₁-C₆alkoxy, and n is 2. Inanother embodiment is a compound of Formula (I) wherein n is 3, and eachR₁ is independently halogen. In another embodiment is a compound ofFormula (I) wherein n is 2, and each R₁ is independently halogen. Inanother embodiment is a compound of Formula (I) wherein n is 2, and eachR₁ is independently F or Cl. In another embodiment is a compound ofFormula (I) wherein n is 2, and each R₁ is F. In another embodiment is acompound of Formula (I) wherein n is 2, and each R₁ is independently Cl.In another embodiment is a compound of Formula (I) wherein n is 2, andeach R₁ is independently halogen or —CF₃. In another embodiment is acompound of Formula (I) wherein n is 2, and each R₁ is independently For —CF₃. In another embodiment is a compound of Formula (I) wherein n is2, and each R₁ is independently Cl or —CF₃. In another embodiment is acompound of Formula (I) wherein n is 1, and R₁ is halogen. In anotherembodiment is a compound of Formula (I) wherein n is 1, and R₁ is F. Inanother embodiment is a compound of Formula (I) wherein n is 1, and R₁is Cl. In another embodiment is a compound of Formula (I) wherein n is1, and R₁ is —CF₃. In another embodiment is a compound of Formula (I)wherein n is 1, and R₁ is substituted or unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (I) wherein n is 1, and R₁is CH₃. In another embodiment is a compound of Formula (I) wherein n is1, and R₁ is substituted or unsubstituted C₁-C₆alkoxy. In anotherembodiment is a compound of Formula (I) wherein n is 1, and R₁ is —OCH₃.In another embodiment is a compound of Formula (I) wherein n is 1, andR₁ is —OCF₃. In another embodiment is a compound of Formula (I) whereinn is 1, and R₁ is —OCF₂H.

In a further embodiment of the aforementioned embodiments of Formula(I), X is C(R₇); Y is N; and Z is N. In a further embodiment of theaforementioned embodiments of Formula (I), X is C(H); Y is N; and Z isN. In a further embodiment of the aforementioned embodiments of Formula(I), X is C(R₇); Y is C(R₇); and Z is N. In a further embodiment of theaforementioned embodiments of Formula (I), X is C(H); Y is C(H); and Zis N. In a further embodiment of the aforementioned embodiments ofFormula (I), X is C(R₇); Y is N; and Z is C(R₇). In a further embodimentof the aforementioned embodiments of Formula (I), X is C(H); Y is N; andZ is C(H). In a further embodiment of the aforementioned embodiments ofFormula (I), X is C(R₇); Y is C(R₇); and Z is C(R₇). In a furtherembodiment of the aforementioned embodiments of Formula (I), X is C(H);Y is C(H); and Z is C(H).

In another aspect, described herein is a compound of Formula (II):

wherein:

-   -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl;    -   or two R₁ are taken together to form a substituted or        unsubstituted heterocyclic ring or a substituted or        unsubstituted carbocyclic ring;    -   R₂ and R₃ are each independently H, —CN, C₁-C₄alkyl,        C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ are        taken together to form a 5- or 6-membered heterocyclic ring;    -   R₅ is halogen, —CN, —OH, —CF₃, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   R₆ is substituted or unsubstituted C₂-C₇heterocycloalkyl,        substituted or unsubstituted C₃-C₈cycloalkyl, substituted or        unsubstituted C₂-C₇heteroaryl, —(C(R₁₄)(R₁₅))_(m)R₂₁, or

-   -   J is C(H);    -   R₁₃ is H, substituted or unsubstituted C₁-C₆alkyl, substituted        or unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        —C₁-C₄alkylC₆-C₁₀aryl, or substituted or unsubstituted        —C₁-C₄alkylC₂-C₇heteroaryl;    -   each R₁₄ and R₁₅ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or    -   R₁₄ and R₁₅ are taken together to form a 4-, 5-, 6-membered        cycloalkyl ring;    -   R₂₁ is halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,        —SR₂₂, —N(R₂₂)S(═O)₂R₂₃, —S(═O)₂N(R₂₂)₂, —S(═O)R₂₃, —S(═O)₂R₂₃,        —C(═O)R₂₃, —CO₂R₂₂, —C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substituted        or unsubstituted C₁-C₆alkoxy, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted C₆-C₁₀aryl, or substituted or        unsubstituted C₂-C₇heteroaryl;    -   each R₂₂ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₂₃ is substituted or unsubstituted C₁-C₆alkyl;    -   each R₈ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₉ is substituted or unsubstituted C₁-C₆alkyl;    -   R₁₀ is H or unsubstituted C₁-C₄alkyl;    -   m is 2-6;    -   n is 0-5;    -   p is 1-3;    -   q is 1-3; or

a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment is a compound of Formula (II) wherein R₆ issubstituted or unsubstituted C₃-C₈cycloalkyl. In another embodiment is acompound of Formula (II) wherein R₆ is substituted or unsubstitutedcyclopropyl. In another embodiment is a compound of Formula (II) whereinR₆ is substituted or unsubstituted cyclobutyl. In another embodiment isa compound of Formula (II) wherein R₆ is substituted or unsubstitutedcyclopentyl. In another embodiment is a compound of Formula (II) whereinR₆ is substituted or unsubstituted cyclohexyl.

In another embodiment is a compound of Formula (II) wherein R₆ issubstituted or unsubstituted C₂-C₇heteroaryl. In another embodiment is acompound of Formula (II) wherein R₆ is substituted or unsubstitutedfuranyl, thiophenyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl,isoxazolyl, isothiazolyl, pyrazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, indolyl,benzothiophenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, pyrazolopyridinyl,imidazopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, indolizinyl,purinyl, furopyridinyl, thienopyridinyl, furopyrrolyl, furofuranyl,thienofuranyl, 1,4-dihydropyrrolopyrrolyl, thienopyrrolyl,thienothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl,furopyrazolyl, thienopyrazolyl, selenophenyl, selenazolyl, andbenzoisoxazolyl. In another embodiment is a compound of Formula (II)wherein R₆ is substituted or unsubstituted pyridyl. In anotherembodiment is a compound of Formula (II) wherein R₆ is substitutedpyridyl. In another embodiment is a compound of Formula (II) wherein R₆is unsubstituted pyridyl.

In another embodiment is a compound of Formula (II) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁. In another embodiment is a compound of Formula(II) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₂₁, and each R₁₄ and R₁₅ are H. Inanother embodiment is a compound of Formula (II) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁, m is 2, and each R₁₄ and R₁₅ are H. In anotherembodiment is a compound of Formula (II) wherein R₆ is —(CH₂)_(m)R₂₁, mis 2, and R₂₁ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (II) wherein R₆ is—(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted or unsubstitutedC₃-C₈cycloalkyl. In another embodiment is a compound of Formula (II)wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted C₆-C₁₀aryl.In another embodiment is a compound of Formula (II) wherein R₆ is—(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted phenyl. In anotherembodiment is a compound of Formula (II) wherein R₆ is —(CH₂)_(m)R₂₁, mis 2, and R₂₁ is substituted or unsubstituted C₂-C₇heteroaryl. Inanother embodiment is a compound of Formula (II) wherein R₆ is—(CH₂)_(m)R₂₁, m is 2, and R₂₁ is —OH. In another embodiment is acompound of Formula (II) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is—N(R₂₂)S(═O)₂R₂₃. In another embodiment is a compound of Formula (II)wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is —N(R₂₂)C(═O)R₂₃. Inanother embodiment is a compound of Formula (II) wherein R₆ is—(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment of the aforementioned embodiments, isa compound of Formula (II) wherein each R₂₂ is independently H orunsubstituted C₁-C₆alkyl; and R₂₃ is unsubstituted C₁-C₆alkyl.

In another embodiment is a compound of Formula (II) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁, m is 3, and each R₁₄ and R₁₅ are H. In anotherembodiment is a compound of Formula (II) wherein R₆ is —(CH₂)_(m)R₂₁, mis 3, and R₂₁ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (II) wherein R₆ is—(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted or unsubstitutedC₃-C₈cycloalkyl. In another embodiment is a compound of Formula (II)wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted C₆-C₁₀aryl.In another embodiment is a compound of Formula (II) wherein R₆ is—(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted phenyl. In anotherembodiment is a compound of Formula (II) wherein R₆ is —(CH₂)_(m)R₂₁, mis 3, and R₂₁ is substituted or unsubstituted C₂-C₇heteroaryl. Inanother embodiment is a compound of Formula (II) wherein R₆ is—(CH₂)_(m)R₂₁, m is 3, and R₂₁ is —OH. In another embodiment is acompound of Formula (II) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is—N(R₂₂)S(═O)₂R₂₃. In another embodiment is a compound of Formula (II)wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is —N(R₂₂)C(═O)R₂₃. Inanother embodiment is a compound of Formula (II) wherein R₆ is—(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment of the aforementioned embodiments, isa compound of Formula (II) wherein each R₂₂ is independently H orunsubstituted C₁-C₆alkyl; and R₂₃ is unsubstituted C₁-C₆alkyl.

In another embodiment is a compound of Formula (II) wherein R₆ issubstituted or unsubstituted C₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (II) wherein R₆ is

and J is C(H). In another embodiment is a compound of Formula (II)wherein R₆ is

J is C(H), p is 1, and q is 1. In another embodiment is a compound ofFormula (II) wherein R₆ is

J is C(H), p is 2, and q is 1. In another embodiment is a compound ofFormula (II) wherein R₆ is

J is C(H), p is 3, and q is 1. In another embodiment is a compound ofFormula (II) wherein R₆ is

J is C(H), p is 2, and q is 2. In another embodiment is a compound ofFormula (II) wherein R₆ is

J is C(H), p is 1, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (II) whereinR₆ is

J is C(H), p is 2, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (II) whereinR₆ is

J is C(H), p is 3, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (II) whereinR₆ is

J is C(H), p is 2, q is 2, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl.

In another embodiment is a compound of Formula (II) wherein R₅ ishalogen. In another embodiment is a compound of Formula (II) wherein R₅is —CF₃. In another embodiment is a compound of Formula (II) wherein R₅is substituted or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (II) wherein R₅ is —CH₃. In another embodiment is acompound of Formula (II) wherein R₅ is —CH₂CH₃. In another embodiment isa compound of Formula (II) wherein R₅ is substituted or unsubstitutedC₁-C₆heteroalkyl. In another embodiment is a compound of Formula (II)wherein R₅ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (II) wherein R₅ issubstituted or unsubstituted C₃-C₈cycloalkyl. In another embodiment is acompound of Formula (II) wherein R₅ is substituted or unsubstitutedC₆-C₁₀aryl. In another embodiment is a compound of Formula (II) whereinR₅ is substituted or unsubstituted C₂-C₇heteroaryl.

In another embodiment is a compound of Formula (II) wherein R₂ and R₃are each independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(II) wherein R₂ and R₃ are each H.

In another embodiment is a compound of Formula (II) wherein R₂ and R₃are each independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl; and at least one of R₂ and R₃ is not H. Inanother embodiment is a compound of Formula (II) wherein R₂ is H, and R₃is C₁-C₄alkyl. In another embodiment is a compound of Formula (II)wherein R₂ is H, and R₃ is CH₃. In another embodiment is a compound ofFormula (II) wherein R₂ is H, and R₃ is C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (II) wherein R₂ is H, and R₃ iscyclopropyl. In another embodiment is a compound of Formula (II) whereinR₂ is H, and R₃ is cyclopentyl. In another embodiment is a compound ofFormula (II) wherein R₂ is CH₃, and R₃ is CH₃. In another embodiment isa compound of Formula (II) wherein R₂ is C₁-C₄alkyl, and R₃ is H. Inanother embodiment is a compound of Formula (II) wherein R₂ is CH₃, andR₃ is H. In another embodiment is a compound of Formula (II) wherein R₂is C₃-C₆cycloalkyl, and R₃ is H. In another embodiment is a compound ofFormula (II) wherein R₂ is cyclopropyl, and R₃ is H. In anotherembodiment is a compound of Formula (II) wherein R₂ is cyclopentyl, andR₃ is H.

In another embodiment is a compound of Formula (II) wherein R₂ and R₃are taken together to form a 5- or 6-membered heterocyclic ring. Inanother embodiment is a compound of Formula (II) wherein R₂ and R₃ aretaken together to form a 5-membered heterocyclic ring. In anotherembodiment is a compound of Formula (II) wherein R₂ and R₃ are takentogether to form 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (II) wherein n is 0.

In another embodiment is a compound of Formula (II) wherein each R₁ isindependently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —SR₈,—N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈,—N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉, substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy, substituted orunsubstituted C₁-C₆heteroalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₃-C₈cycloalkyl,substituted or unsubstituted C₆-C₁₀aryl, or substituted or unsubstitutedC₂-C₇heteroaryl. In another embodiment is a compound of Formula (II)wherein each R₁ is independently halogen, —CN, —OH, substituted orunsubstituted C₁-C₆alkyl, or substituted or unsubstituted C₁-C₆alkoxy.In another embodiment is a compound of Formula (II) wherein each R₁ isindependently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (II) wherein each R₁ is independently halogen, —CN, —OCF₃,—OCH₂F, —OCF₂H, substituted or unsubstituted C₁-C₆alkyl, or substitutedor unsubstituted C₁-C₆alkoxy. In another embodiment is a compound ofFormula (II) wherein each R₁ is independently halogen, —CN, —OCF₃,—OCH₂F, —OCF₂H, substituted or unsubstituted C₁-C₆alkyl, or substitutedor unsubstituted C₁-C₆alkoxy, and n is 3. In another embodiment is acompound of Formula (II) wherein each R₁ is independently halogen, —CN,—OCF₃, —OCH₂F, —OCF₂H, substituted or unsubstituted C₁-C₆alkyl, orsubstituted or unsubstituted C₁-C₆alkoxy, and n is 2. In anotherembodiment is a compound of Formula (II) wherein n is 3, and each R₁ isindependently halogen. In another embodiment is a compound of Formula(II) wherein n is 2, and each R₁ is independently halogen. In anotherembodiment is a compound of Formula (II) wherein n is 2, and each R₁ isindependently F or Cl. In another embodiment is a compound of Formula(II) wherein n is 2, and each R₁ is F. In another embodiment is acompound of Formula (II) wherein n is 2, and each R₁ is independentlyCl. In another embodiment is a compound of Formula (II) wherein n is 1,and R₁ is halogen. In another embodiment is a compound of Formula (II)wherein n is 1, and R₁ is F. In another embodiment is a compound ofFormula (II) wherein n is 1, and R₁ is Cl. In another embodiment is acompound of Formula (II) wherein n is 1, and R₁ is substituted orunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(II) wherein n is 1, and R₁ is CH₃. In another embodiment is a compoundof Formula (II) wherein n is 1, and R₁ is substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment is a compound of Formula (II) whereinn is 1, and R₁ is —OCH₃. In another embodiment is a compound of Formula(II) wherein n is 1, and R₁ is —OCF₃. In another embodiment is acompound of Formula (II) wherein n is 1, and R₁ is —OCF₂H.

In another embodiment, described herein is a compound of Formula (IIA):

wherein:

-   -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl;    -   or two R₁ are taken together to form a substituted or        unsubstituted heterocyclic ring or a substituted or        unsubstituted carbocyclic ring;    -   R₂ and R₃ are each independently H, —CN, C₁-C₄alkyl,        C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ are        taken together to form a 5- or 6-membered heterocyclic ring;    -   R₄ is H, halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —SR₈,        —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉, —C(═O)R₉,        —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted        or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl; or        two R₁ are taken together to form a substituted or unsubstituted        heterocyclic ring or a substituted or unsubstituted carbocyclic        ring; wherein when n is 0, R₄ is not halogen;    -   R₅ is halogen, —CN, —OH, —CF₃, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂);    -   R₁₁ and R₁₂ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or R₁₁ and R₁₂ are taken together to        form a 5-, 6-, 7-, or 8-membered heterocyclic ring;    -   R₁₃ is H, substituted or unsubstituted C₁-C₆alkyl, substituted        or unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        —C₁-C₄alkylC₆-C₁₀aryl, or substituted or unsubstituted        —C₁-C₄alkyC₂-C₇heteroaryl;    -   each R₁₄ and R₁₅ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or    -   R₁₄ and R₁₅ are taken together to form a 4-, 5-, 6-membered        cycloalkyl ring;    -   each R₈ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₉ is substituted or unsubstituted C₁-C₆alkyl;    -   R₁₀ is H, or C₁-C₄alkyl;    -   m is 2-6;    -   n is 0-4; or

a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In one embodiment is a compound of Formula (IIA) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), and each R₁₄ and R₁₅ are H. In anotherembodiment is a compound of Formula (IIA) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), and R₁₁ and R₁₂ are each H. In another embodimentis a compound of Formula (IIA) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), R₁₁is substituted or unsubstituted C₁-C₆ alkyl, and R₁₂ is H. In anotherembodiment is a compound of Formula (IIA) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), R₁₁ is CH₃, and R₁₂ is H. In another embodimentis a compound of Formula (IIA) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), R₁₁is substituted or unsubstituted C₁-C₆alkyl, and R₁₂ is substituted orunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIA) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), R₁₁ is CH₃, and R₁₂ is CH₃.In another embodiment is a compound of Formula (IIA) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), and R₁₁ and R₁₂ are taken together to form a 5-,6-, 7-, or 8-membered heterocyclic ring. In another embodiment is acompound of Formula (IIA) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), and R₁₁and R₁₂ are taken together to form a 5-membered heterocyclic ring. Inanother embodiment is a compound of Formula (IIA) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), and R₁₁ and R₁₂ are taken together to form a6-membered heterocyclic ring.

In another embodiment is a compound of Formula (IIA) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), m is 2, and each R₁₄ and R₁₅ are H. Inanother embodiment is a compound of Formula (IIA) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ are each H. In anotherembodiment is a compound of Formula (IIA) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is H. In another embodiment is a compound of Formula(IIA) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is CH₃, and R₁₂is H. In another embodiment is a compound of Formula (IIA) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is substituted or unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIA) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is CH₃, and R₁₂ is CH₃. In anotherembodiment is a compound of Formula (IIA) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ are taken together toform a 5-, 6-, 7-, or 8-membered heterocyclic ring. In anotherembodiment is a compound of Formula (IIA) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ are taken together toform a 5-membered heterocyclic ring. In another embodiment is a compoundof Formula (IIA) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁and R₁₂ are taken together to form a 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (IIA) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂). In another embodiment is a compound ofFormula (IIA) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), m is 3, andeach R₁₄ and R₁₅ are H. In another embodiment is a compound of Formula(IIA) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ areeach H. In another embodiment is a compound of Formula (IIA) wherein R₆is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is H. In another embodiment is a compound of Formula(IIA) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is CH₃, and R₁₂is H. In another embodiment is a compound of Formula (IIA) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is substituted or unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIA) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is CH₃, and R₁₂ is CH₃. In anotherembodiment is a compound of Formula (IIA) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ are taken together toform a 5-, 6-, 7-, or 8-membered heterocyclic ring. In anotherembodiment is a compound of Formula (IIA) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ are taken together toform a 5-membered heterocyclic ring. In another embodiment is a compoundof Formula (IIA) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁and R₁₂ are taken together to form a 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (IIA) wherein R₅ ishalogen. In another embodiment is a compound of Formula (IIA) wherein R₅is —CF₃. In another embodiment is a compound of Formula (IIA) wherein R₅is substituted or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (IIA) wherein R₅ is —CH₃. In another embodiment is acompound of Formula (IIA) wherein R₅ is —CH₂CH₃. In another embodimentis a compound of Formula (IIA) wherein R₅ is substituted orunsubstituted C₁-C₆heteroalkyl. In another embodiment is a compound ofFormula (IIA) wherein R₅ is substituted or unsubstitutedC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(IIA) wherein R₅ is substituted or unsubstituted C₃-C₈cycloalkyl. Inanother embodiment is a compound of Formula (IIA) wherein R₅ issubstituted or unsubstituted C₆-C₁₀aryl. In another embodiment is acompound of Formula (IIA) wherein R₅ is substituted or unsubstitutedC₂-C₇heteroaryl.

In another embodiment is a compound of Formula (IIA) wherein R₂ and R₃are each independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(IIA) wherein R₂ and R₃ are each H.

In another embodiment is a compound of Formula (IIA) wherein R₂ and R₃are each independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl; and at least one of R₂ and R₃ is not H. Inanother embodiment is a compound of Formula (IIA) wherein R₂ is H, andR₃ is C₁-C₄alkyl. In another embodiment is a compound of Formula (IIA)wherein R₂ is H, and R₃ is CH₃. In another embodiment is a compound ofFormula (IIA) wherein R₂ is H, and R₃ is C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (IIA) wherein R₂ is H, and R₃ iscyclopropyl. In another embodiment is a compound of Formula (IIA)wherein R₂ is H, and R₃ is cyclopentyl. In another embodiment is acompound of Formula (IIA) wherein R₂ is CH₃, and R₃ is CH₃. In anotherembodiment is a compound of Formula (IIA) wherein R₂ is C₁-C₄alkyl, andR₃ is H. In another embodiment is a compound of Formula (IIA) wherein R₂is CH₃, and R₃ is H. In another embodiment is a compound of Formula(IIA) wherein R₂ is C₃-C₆cycloalkyl, and R₃ is H. In another embodimentis a compound of Formula (IIA) wherein R₂ is cyclopropyl, and R₃ is H.In another embodiment is a compound of Formula (IIA) wherein R₂ iscyclopentyl, and R₃ is H.

In another embodiment is a compound of Formula (IIA) wherein R₂ and R₃are taken together to form a 5- or 6-membered heterocyclic ring. Inanother embodiment is a compound of Formula (IIA) wherein R₂ and R₃ aretaken together to form a 5-membered heterocyclic ring. In anotherembodiment is a compound of Formula (IIA) wherein R₂ and R₃ are takentogether to form 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (IIA) wherein n is 0.

In another embodiment is a compound of Formula (IIA) wherein each R₁ isindependently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —SR₈,—N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈,—N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉, substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy, substituted orunsubstituted C₁-C₆heteroalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₃-C₈cycloalkyl,substituted or unsubstituted C₆-C₁₀aryl, or substituted or unsubstitutedC₂-C₇heteroaryl. In another embodiment is a compound of Formula (IIA)wherein each R₁ is independently halogen, —CN, —OH, substituted orunsubstituted C₁-C₆alkyl, or substituted or unsubstituted C₁-C₆alkoxy.In another embodiment is a compound of Formula (IIA) wherein each R₁ isindependently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (IIA) wherein each R₁ is independently halogen, —CN, —OCF₃,—OCH₂F, —OCF₂H, substituted or unsubstituted C₁-C₆alkyl, or substitutedor unsubstituted C₁-C₆alkoxy. In another embodiment is a compound ofFormula (IIA) wherein each R₁ is independently halogen, —CN, —OCF₃,—OCH₂F, —OCF₂H, substituted or unsubstituted C₁-C₆alkyl, or substitutedor unsubstituted C₁-C₆alkoxy, and n is 3. In another embodiment is acompound of Formula (IIA) wherein each R₁ is independently halogen, —CN,—OCF₃, —OCH₂F, —OCF₂H, substituted or unsubstituted C₁-C₆alkyl, orsubstituted or unsubstituted C₁-C₆alkoxy, and n is 2. In anotherembodiment is a compound of Formula (IIA) wherein n is 3, and each R₁ isindependently halogen. In another embodiment is a compound of Formula(IIA) wherein n is 2, and each R₁ is independently halogen. In anotherembodiment is a compound of Formula (IIA) wherein n is 2, and each R₁ isindependently F or Cl. In another embodiment is a compound of Formula(IIA) wherein n is 2, and each R₁ is F. In another embodiment is acompound of Formula (IIA) wherein n is 2, and each R₁ is independentlyCl. In another embodiment is a compound of Formula (IIA) wherein n is 1,and R₁ is halogen. In another embodiment is a compound of Formula (IIA)wherein n is 1, and R₁ is F. In another embodiment is a compound ofFormula (IIA) wherein n is 1, and R₁ is Cl. In another embodiment is acompound of Formula (IIA) wherein n is 1, and R₁ is substituted orunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIA) wherein n is 1, and R₁ is CH₃. In another embodiment is a compoundof Formula (IIA) wherein n is 1, and R₁ is substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment is a compound of Formula (IIA)wherein n is 1, and R₁ is —OCH₃. In another embodiment is a compound ofFormula (IIA) wherein n is 1, and R₁ is —OCF₃. In another embodiment isa compound of Formula (IIA) wherein n is 1, and R₁ is —OCF₂H.

In another embodiment is a compound of Formula (IIA) wherein R₄ is H,halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —SR₈, —N(R₈)S(═O)₂R₉,—S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂,—C(═O)N(R₈)₂, —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl, orsubstituted or unsubstituted C₁-C₆alkoxy. In another embodiment is acompound of Formula (IIA) wherein R₄ is H, halogen, —CN, —OH, —OCF₃,substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment is a compound of Formula (IIA)wherein R₄ is H. In another embodiment is a compound of Formula (IIA)wherein R₄ is halogen. In another embodiment is a compound of Formula(IIA) wherein R₄ is F. In another embodiment is a compound of Formula(IIA) wherein R₄ is Cl. In another embodiment is a compound of Formula(IIA) wherein R₄ is Br. In another embodiment is a compound of Formula(IIA) wherein R₄ is —CF₃. In another embodiment is a compound of Formula(IIA) wherein R₄ is —OCF₃. In another embodiment is a compound ofFormula (IIA) R₄ is —CH₃. In another embodiment is a compound of Formula(IIA) wherein R₄ is —OCH₃.

In another embodiment is a compound of Formula (IIA) wherein n is 0 andR₄ is H. In another embodiment is a compound of Formula (IIA) wherein nis 0 and R₄ is halogen. In another embodiment is a compound of Formula(IIA) wherein n is 0 and R₄ is F. In another embodiment is a compound ofFormula (IIA) wherein n is 0 and R₄ is Cl. In another embodiment is acompound of Formula (IIA) wherein n is 0 and R₄ is Br. In anotherembodiment is a compound of Formula (IIA) wherein n is 0 and R₄ is —CF₃.In another embodiment is a compound of Formula (IIA) wherein n is 0 andR₄ is —OCF₃. In another embodiment is a compound of Formula (IIA)wherein n is 0 and R₄ is —CH₃. In another embodiment is a compound ofFormula (IIA) wherein n is 0 and R₄ is —OCH₃.

In another embodiment is a compound of Formula (IIA) wherein n is 1, R₁is Cl, and R₄ is Cl. In another embodiment is a compound of Formula(IIA) wherein n is 1, R₁ is —CH₃, and R₄ is Cl. In another embodiment isa compound of Formula (IIA) wherein n is 1, R₁ is —OCH₃, and R₄ is Cl.In another embodiment is a compound of Formula (IIA) wherein n is 1, R₁is —CF₃, and R₄ is Cl. In another embodiment is a compound of Formula(IIA) wherein n is 1, R₁ is —OCF₃, and R₄ is Cl. In another embodimentis a compound of Formula (IIA) wherein n is 1, R₁ is Cl, and R₄ is F. Inanother embodiment is a compound of Formula (IIA) wherein n is 1, R₁ is—CH₃, and R₄ is F. In another embodiment is a compound of Formula (IIA)wherein n is 1, R₁ is —OCH₃, and R₄ is F. In another embodiment is acompound of Formula (IIA) wherein n is 1, R₁ is —CF₃, and R₄ is F. Inanother embodiment is a compound of Formula (IIA) wherein n is 1, R₁ is—OCF₃, and R₄ is F. In another embodiment is a compound of Formula (IIA)wherein n is 1, R₁ is Cl, and R₄ is H. In another embodiment is acompound of Formula (IIA) wherein n is 1, R₁ is —CH₃, and R₄ is H. Inanother embodiment is a compound of Formula (IIA) wherein n is 1, R₁ is—OCH₃, and R₄ is H. In another embodiment is a compound of Formula (IIA)wherein n is 1, R₁ is —CF₃, and R₄ is H. In another embodiment is acompound of Formula (IIA) wherein n is 1, R₁ is —OCF₃, and R₄ is H. Inanother embodiment is a compound of Formula (IIA) wherein n is 1, R₁ isCl, and R₄ is —OCH₃. In another embodiment is a compound of Formula(IIA) wherein n is 1, R₁ is —CH₃, and R₄ is —OCH₃. In another embodimentis a compound of Formula (IIA) wherein n is 1, R₁ is —OCH₃, and R₄ is—OCH₃. In another embodiment is a compound of Formula (IIA) wherein n is1, R₁ is —CF₃, and R₄ is —OCH₃. In another embodiment is a compound ofFormula (IIA) wherein n is 1, R₁ is —OCF₃, and R₄ is —OCH₃. In anotherembodiment is a compound of Formula (IIA) wherein n is 1, R₁ is Cl, andR₄ is —OCF₃. In another embodiment is a compound of Formula (IIA)wherein n is 1, R₁ is —CH₃, and R₄ is —OCF₃. In another embodiment is acompound of Formula (IIA) wherein n is 1, R₁ is —OCH₃, and R₄ is —OCF₃.In another embodiment is a compound of Formula (IIA) wherein n is 1, R₁is —CF₃, and R₄ is —OCF₃. In another embodiment is a compound of Formula(IIA) wherein n is 1, R₁ is —OCF₃, and R₄ is —OCF₃.

In another embodiment, described herein is a compound of Formula (IIA′):

wherein:

-   -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl;    -   or two R₁ are taken together to form a substituted or        unsubstituted heterocyclic ring or a substituted or        unsubstituted carbocyclic ring;    -   R₂ and R₃ are each independently H, —CN, C₁-C₄alkyl,        C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ are        taken together to form a 5- or 6-membered heterocyclic ring;    -   R₄ is H, F, Cl, Br, I, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H,        —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉,        —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉,        substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆alkoxy, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl; or two R₁ are        taken together to form a substituted or unsubstituted        heterocyclic ring or a substituted or unsubstituted carbocyclic        ring; wherein when n is 0, R₄ is not Cl;    -   R₅ is halogen, —CN, —OH, —CF₃, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂);    -   R₁₁ and R₁₂ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or R₁₁ and R₁₂ are taken together to        form a 5-, 6-, 7-, or 8-membered heterocyclic ring;    -   R₁₃ is H, substituted or unsubstituted C₁-C₆alkyl, substituted        or unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        —C₁-C₄alkylC₆-C₁₀aryl, or substituted or unsubstituted        —C₁-C₄alkyC₂-C₇heteroaryl;    -   each R₁₄ and R₁₅ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or    -   R₁₄ and R₁₅ are taken together to form a 4-, 5-, 6-membered        cycloalkyl ring;    -   each R₈ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₉ is substituted or unsubstituted C₁-C₆alkyl;    -   R₁₀ is H, or C₁-C₄alkyl;    -   m is 2-6;    -   n is 0-4; or

a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, described herein is a compound of Formula (IIB):

wherein:

-   -   A is O;    -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl;    -   or two R₁ are taken together to form a substituted or        unsubstituted heterocyclic ring or a substituted or        unsubstituted carbocyclic ring;    -   R₂ and R₃ are each independently H, —CN, C₁-C₄alkyl,        C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ are        taken together to form a 5- or 6-membered heterocyclic ring;    -   R₅ is halogen, —CN, —OH, —CF₃, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   R₆ is substituted or unsubstituted C₂-C₇heterocycloalkyl,        substituted or unsubstituted C₃-C₈cycloalkyl, substituted or        unsubstituted C₂-C₇heteroaryl, —(C(R₁₄)(R₁₅))_(m)R₂₁,        —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), or

-   -   R₁₁ and R₁₂ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or R₁₁ and R₁₂ are taken together to        form a 5-, 6-, 7-, or 8-membered heterocyclic ring;    -   J is C(H);    -   R₁₃ is H, substituted or unsubstituted C₁-C₆alkyl, substituted        or unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        —C₁-C₄alkylC₆-C₁₀aryl, or substituted or unsubstituted        —C₁-C₄alkylC₂-C₇heteroaryl;    -   each R₁₄ and R₁₅ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or    -   R₁₄ and R₁₅ are taken together to form a 4-, 5-, 6-membered        cycloalkyl ring;    -   R₂₁ is halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,        —SR₂₂, —N(R₂₂)S(═O)₂R₂₃, —S(═O)₂N(R₂₂)₂, —S(═O)R₂₃, —S(═O)₂R₂₃,        —C(═O)R₂₃, —CO₂R₂₂, —C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted        or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   each R₂₂ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₂₃ is substituted or unsubstituted C₁-C₆alkyl;    -   each R₈ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₉ is substituted or unsubstituted C₁-C₆alkyl;    -   m is 2-6;    -   n is 0-5;    -   p is 1-3;    -   q is 1-3; or

a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment is a compound of Formula (IIB) wherein R₆ issubstituted or unsubstituted C₃-C₈cycloalkyl. In another embodiment is acompound of Formula (IIB) wherein R₆ is substituted or unsubstitutedcyclopropyl. In another embodiment is a compound of Formula (IIB)wherein R₆ is substituted or unsubstituted cyclobutyl. In anotherembodiment is a compound of Formula (IIB) wherein R₆ is substituted orunsubstituted cyclopentyl. In another embodiment is a compound ofFormula (IIB) wherein R₆ is substituted or unsubstituted cyclohexyl.

In another embodiment is a compound of Formula (IIB) wherein R₆ issubstituted or unsubstituted C₂-C₇heteroaryl. In another embodiment is acompound of Formula (IIB) wherein R₆ is substituted or unsubstitutedfuranyl, thiophenyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl,isoxazolyl, isothiazolyl, pyrazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, indolyl,benzothiophenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, pyrazolopyridinyl,imidazopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, indolizinyl,purinyl, furopyridinyl, thienopyridinyl, furopyrrolyl, furofuranyl,thienofuranyl, 1,4-dihydropyrrolopyrrolyl, thienopyrrolyl,thienothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl,furopyrazolyl, thienopyrazolyl, selenophenyl, selenazolyl, andbenzoisoxazolyl. In another embodiment is a compound of Formula (IIB)wherein R₆ is substituted or unsubstituted pyridyl. In anotherembodiment is a compound of Formula (IIB) wherein R₆ is substitutedpyridyl. In another embodiment is a compound of Formula (IIB) wherein R₆is unsubstituted pyridyl.

In another embodiment is a compound of Formula (IIB) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁. In another embodiment is a compound of Formula(IIB) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₂₁, and each R₁₄ and R₁₅ are H.In another embodiment is a compound of Formula (IIB) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁, m is 2, and each R₁₄ and R₁₅ are H. In anotherembodiment is a compound of Formula (I) wherein R₆ is —(CH₂)_(m)R₂₁, mis 2, and R₂₁ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (IIB) wherein R₆ is—(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted or unsubstitutedC₃-C₈cycloalkyl. In another embodiment is a compound of Formula (IIB)wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted orunsubstituted C₆-C₁₀aryl. In another embodiment is a compound of Formula(IIB) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted orunsubstituted phenyl. In another embodiment is a compound of Formula(IIB) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted orunsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (IIB) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is —OH.

In another embodiment is a compound of Formula (IIB) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁, m is 3, and each R₁₄ and R₁₅ are H. In anotherembodiment is a compound of Formula (IIB) wherein R₆ is —(CH₂)_(m)R₂₁, mis 3, and R₂₁ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (IIB) wherein R₆ is—(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted or unsubstitutedC₃-C₈cycloalkyl. In another embodiment is a compound of Formula (IIB)wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted orunsubstituted C₆-C₁₀aryl. In another embodiment is a compound of Formula(IIB) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted orunsubstituted phenyl. In another embodiment is a compound of Formula(IIB) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted orunsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (IIB) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is —OH.

In another embodiment is a compound of Formula (IIB) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂). In another embodiment is a compound ofFormula (IIB) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), m is 2, andeach R₁₄ and R₁₅ are H. In another embodiment is a compound of Formula(IIB) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ areeach H. In another embodiment is a compound of Formula (IIB) wherein R₆is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is H. In another embodiment is a compound of Formula(IIB) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is CH₃, and R₁₂is H. In another embodiment is a compound of Formula (IIB) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is substituted or unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIB) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is CH₃, and R₁₂ is CH₃. In anotherembodiment is a compound of Formula (IIB) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ are taken together toform a 5-, 6-, 7-, or 8-membered heterocyclic ring. In anotherembodiment is a compound of Formula (IIB) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ are taken together toform a 5-membered heterocyclic ring. In another embodiment is a compoundof Formula (IIB) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁and R₁₂ are taken together to form a 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (IIB) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂). In another embodiment is a compound ofFormula (IIB) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), m is 3, andeach R₁₄ and R₁₅ are H. In another embodiment is a compound of Formula(IIB) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ areeach H. In another embodiment is a compound of Formula (IIB) wherein R₆is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 23, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is H. In another embodiment is a compound of Formula(IIB) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is CH₃, and R₁₂is H. In another embodiment is a compound of Formula (IIB) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is substituted or unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIB) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is CH₃, and R₁₂ is CH₃. In anotherembodiment is a compound of Formula (IIB) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ are taken together toform a 5-, 6-, 7-, or 8-membered heterocyclic ring. In anotherembodiment is a compound of Formula (IIB) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ are taken together toform a 5-membered heterocyclic ring. In another embodiment is a compoundof Formula (IIB) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁and R₁₂ are taken together to form a 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (IIB) wherein R₆ issubstituted or unsubstituted C₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (IIB) wherein R₆ is

and J is C(H). In another embodiment is a compound of Formula (IIB)wherein R₆ is

J is C(H), p is 1, and q is 1. In another embodiment is a compound ofFormula (IIB) wherein R₆ is

J is C(H), p is 2, and q is 1. In another embodiment is a compound ofFormula (IIB) wherein R₆ is

J is C(H), p is 3, and q is 1. In another embodiment is a compound ofFormula (IIB) wherein R₆ is

J is C(H), p is 2, and q is 2. In another embodiment is a compound ofFormula (IIB) wherein R₆ is

J is C(H), p is 1, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIB) whereinR₆ is

J is C(H), p is 2, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIB) whereinR₆ is

J is C(H), p is 3, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIB) whereinR₆ is

J is C(H), p is 2, q is 2, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl.

In another embodiment is a compound of Formula (IIB) wherein R₈ ishalogen. In another embodiment is a compound of Formula (IIB) wherein R₈is —CF₃. In another embodiment is a compound of Formula (IIB) wherein R₈is substituted or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (IIB) wherein R₈ is —CH₃. In another embodiment is acompound of Formula (IIB) wherein R₈ is —CH₂CH₃. In another embodimentis a compound of Formula (IIB) wherein R₈ is substituted orunsubstituted C₁-C₆heteroalkyl. In another embodiment is a compound ofFormula (IIB) wherein R₈ is substituted or unsubstitutedC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(IIB) wherein R₅ is substituted or unsubstituted C₃-C₈cycloalkyl. Inanother embodiment is a compound of Formula (IIB) wherein R₅ issubstituted or unsubstituted C₆-C₁₀aryl. In another embodiment is acompound of Formula (IIB) wherein R₅ is substituted or unsubstitutedC₂-C₇heteroaryl.

In another embodiment is a compound of Formula (IIB) wherein R₂ and R₃are each independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(IIB) wherein R₂ and R₃ are each H.

In another embodiment is a compound of Formula (IIB) wherein R₂ and R₃are each independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl; and at least one of R₂ and R₃ is not H. Inanother embodiment is a compound of Formula (IIB) wherein R₂ is H, andR₃ is C₁-C₄alkyl. In another embodiment is a compound of Formula (IIB)wherein R₂ is H, and R₃ is CH₃. In another embodiment is a compound ofFormula (IIB) wherein R₂ is H, and R₃ is C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (IIB) wherein R₂ is H, and R₃ iscyclopropyl. In another embodiment is a compound of Formula (IIB)wherein R₂ is H, and R₃ is cyclopentyl. In another embodiment is acompound of Formula (IIB) wherein R₂ is CH₃, and R₃ is CH₃. In anotherembodiment is a compound of Formula (IIB) wherein R₂ is C₁-C₄alkyl, andR₃ is H. In another embodiment is a compound of Formula (IIB) wherein R₂is CH₃, and R₃ is H. In another embodiment is a compound of Formula(IIB) wherein R₂ is C₃-C₆cycloalkyl, and R₃ is H. In another embodimentis a compound of Formula (IIB) wherein R₂ is cyclopropyl, and R₃ is H.In another embodiment is a compound of Formula (IIB) wherein R₂ iscyclopentyl, and R₃ is H.

In another embodiment is a compound of Formula (IIB) wherein R₂ and R₃are taken together to form a 5- or 6-membered heterocyclic ring. Inanother embodiment is a compound of Formula (IIB) wherein R₂ and R₃ aretaken together to form a 5-membered heterocyclic ring. In anotherembodiment is a compound of Formula (IIB) wherein R₂ and R₃ are takentogether to form 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (IIB) wherein n is 0.

In another embodiment is a compound of Formula (IIB) wherein each R₁ isindependently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,—SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉, —C(═O)R₉,—CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (IIB) wherein each R₁ is independently halogen, —CN, —OH, —CF₃,substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment is a compound of Formula (IIB)wherein each R₁ is independently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H,—CF₃, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkoxy, substituted or unsubstitutedC₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl,substituted or unsubstituted C₃-C₈cycloalkyl, substituted orunsubstituted C₆-C₁₀aryl, or substituted or unsubstitutedC₂-C₇heteroaryl. In another embodiment is a compound of Formula (IIB)wherein each R₁ is independently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H,—CF₃, substituted or unsubstituted C₁-C₆alkyl, or substituted orunsubstituted C₁-C₆alkoxy. In another embodiment is a compound ofFormula (IIB) wherein each R₁ is independently halogen, —CN, —OCF₃,—OCH₂F, —OCF₂H, —CF₃, substituted or unsubstituted C₁-C₆alkyl, orsubstituted or unsubstituted C₁-C₆alkoxy, and n is 3. In anotherembodiment is a compound of Formula (IIB) wherein each R₁ isindependently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H, —CF₃, substituted orunsubstituted C₁-C₆alkyl, or substituted or unsubstituted C₁-C₆alkoxy,and n is 2. In another embodiment is a compound of Formula (IIB) whereinn is 3, and each R₁ is independently halogen. In another embodiment is acompound of Formula (IIB) wherein n is 2, and each R₁ is independentlyhalogen. In another embodiment is a compound of Formula (IIB) wherein nis 2, and each R₁ is independently F or Cl. In another embodiment is acompound of Formula (IIB) wherein n is 2, and each R₁ is F. In anotherembodiment is a compound of Formula (IIB) wherein n is 2, and each R₁ isindependently Cl. In another embodiment is a compound of Formula (IIB)wherein n is 2, and each R₁ is independently halogen or —CF₃. In anotherembodiment is a compound of Formula (IIB) wherein n is 2, and each R₁ isindependently F or —CF₃. In another embodiment is a compound of Formula(IIB) wherein n is 2, and each R₁ is independently Cl or —CF₃. Inanother embodiment is a compound of Formula (IIB) wherein n is 1, and R₁is halogen. In another embodiment is a compound of Formula (IIB) whereinn is 1, and R₁ is F. In another embodiment is a compound of Formula(IIB) wherein n is 1, and R₁ is Cl. In another embodiment is a compoundof Formula (IIB) wherein n is 1, and R₁ is —CF₃. In another embodimentis a compound of Formula (IIB) wherein n is 1, and R₁ is substituted orunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIB) wherein n is 1, and R₁ is CH₃. In another embodiment is a compoundof Formula (IIB) wherein n is 1, and R₁ is substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment is a compound of Formula (IIB)wherein n is 1, and R₁ is —OCH₃. In another embodiment is a compound ofFormula (IIB) wherein n is 1, and R₁ is —OCF₃. In another embodiment isa compound of Formula (IIB) wherein n is 1, and R₁ is —OCF₂H.

In another embodiment, described herein is a compound of Formula (IIC):

wherein:

-   -   A is a bond;    -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl;    -   or two R₁ are taken together to form a substituted or        unsubstituted heterocyclic ring or a substituted or        unsubstituted carbocyclic ring;    -   R₂ and R₃ are each independently H, —CN, C₁-C₄alkyl,        C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ are        taken together to form a 5- or 6-membered heterocyclic ring;    -   R₅ is halogen, —CN, —OH, —CF₃, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   R₆ is substituted or unsubstituted C₃-C₈cycloalkyl, substituted        or unsubstituted C₂-C₇heteroaryl, —(C(R₁₄)(R₁₅))_(m)R₂₁,        —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), or

-   -   R₁₁ and R₁₂ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or R₁₁ and R₁₂ are taken together to        form a 5-, 6-, 7-, or 8-membered heterocyclic ring;    -   J is C(H);    -   R₁₃ is H, substituted or unsubstituted C₁-C₆alkyl, substituted        or unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        —C₁-C₄alkylC₆-C₁₀aryl, or substituted or unsubstituted        —C₁-C₄alkylC₂-C₇heteroaryl;    -   each R₁₄ and R₁₅ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or    -   R₁₄ and R₁₅ are taken together to form a 4-, 5-, 6-membered        cycloalkyl ring;    -   R₂₁ is halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,        —SR₂₂, —N(R₂₂)S(═O)₂R₂₃, —S(═O)₂N(R₂₂)₂, —S(═O)R₂₃, —S(═O)₂R₂₃,        —C(═O)R₂₃, —CO₂R₂₂, —C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted        or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   each R₂₂ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₂₃ is substituted or unsubstituted C₁-C₆alkyl;    -   each R₈ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₉ is substituted or unsubstituted C₁-C₆alkyl;    -   m is 2-6;    -   n is 0-5;    -   p is 1-3;    -   q is 1-3; or

a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment is a compound of Formula (IIC) wherein R₆ issubstituted or unsubstituted C₃-C₈cycloalkyl. In another embodiment is acompound of Formula (IIC) wherein R₆ is substituted or unsubstitutedcyclopropyl. In another embodiment is a compound of Formula (IIC)wherein R₆ is substituted or unsubstituted cyclobutyl. In anotherembodiment is a compound of Formula (IIC) wherein R₆ is substituted orunsubstituted cyclopentyl. In another embodiment is a compound ofFormula (IIC) wherein R₆ is substituted or unsubstituted cyclohexyl.

In another embodiment is a compound of Formula (IIC) wherein R₆ issubstituted or unsubstituted C₂-C₇heteroaryl. In another embodiment is acompound of Formula (IIC) wherein R₆ is substituted or unsubstitutedfuranyl, thiophenyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl,isoxazolyl, isothiazolyl, pyrazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, indolyl,benzothiophenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, pyrazolopyridinyl,imidazopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, indolizinyl,purinyl, furopyridinyl, thienopyridinyl, furopyrrolyl, furofuranyl,thienofuranyl, 1,4-dihydropyrrolopyrrolyl, thienopyrrolyl,thienothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl,furopyrazolyl, thienopyrazolyl, selenophenyl, selenazolyl, andbenzoisoxazolyl. In another embodiment is a compound of Formula (IIC)wherein R₆ is substituted or unsubstituted pyridyl. In anotherembodiment is a compound of Formula (IIC) wherein R₆ is substitutedpyridyl. In another embodiment is a compound of Formula (IIC) wherein R₆is unsubstituted pyridyl.

In another embodiment is a compound of Formula (IIC) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁. In another embodiment is a compound of Formula(IIC) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₂₁, and each R₁₄ and R₁₅ are H.In another embodiment is a compound of Formula (IIC) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁, m is 2, and each R₁₄ and R₁₅ are H. In anotherembodiment is a compound of Formula (I) wherein R₆ is —(CH₂)_(m)R₂₁, mis 2, and R₂₁ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (IIC) wherein R₆ is—(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted or unsubstitutedC₃-C₈cycloalkyl. In another embodiment is a compound of Formula (IIC)wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted orunsubstituted C₆-C₁₀aryl. In another embodiment is a compound of Formula(IIC) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted orunsubstituted phenyl. In another embodiment is a compound of Formula(IIC) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted orunsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (IIC) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is —OH.

In another embodiment is a compound of Formula (IIC) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁, m is 3, and each R₁₄ and R₁₅ are H. In anotherembodiment is a compound of Formula (IIC) wherein R₆ is —(CH₂)_(m)R₂₁, mis 3, and R₂₁ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (IIC) wherein R₆ is—(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted or unsubstitutedC₃-C₈cycloalkyl. In another embodiment is a compound of Formula (IIC)wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted orunsubstituted C₆-C₁₀aryl. In another embodiment is a compound of Formula(IIC) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted orunsubstituted phenyl. In another embodiment is a compound of Formula(IIC) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted orunsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (IIC) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is —OH.

In another embodiment is a compound of Formula (IIC) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂). In another embodiment is a compound ofFormula (IIC) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), m is 2, andeach R₁₄ and R₁₅ are H. In another embodiment is a compound of Formula(IIC) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ areeach H. In another embodiment is a compound of Formula (IIC) wherein R₆is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is H. In another embodiment is a compound of Formula(IIC) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is CH₃, and R₁₂is H. In another embodiment is a compound of Formula (IIC) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is substituted or unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIC) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is CH₃, and R₁₂ is CH₃. In anotherembodiment is a compound of Formula (IIC) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ are taken together toform a 5-, 6-, 7-, or 8-membered heterocyclic ring. In anotherembodiment is a compound of Formula (IIC) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ are taken together toform a 5-membered heterocyclic ring. In another embodiment is a compoundof Formula (IIC) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁and R₁₂ are taken together to form a 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (IIC) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂). In another embodiment is a compound ofFormula (IIC) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), m is 3, andeach R₁₄ and R₁₅ are H. In another embodiment is a compound of Formula(IIC) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ areeach H. In another embodiment is a compound of Formula (IIC) wherein R₆is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 23, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is H. In another embodiment is a compound of Formula(IIC) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is CH₃, and R₁₂is H. In another embodiment is a compound of Formula (IIC) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is substituted or unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIC) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is CH₃, and R₁₂ is CH₃. In anotherembodiment is a compound of Formula (IIC) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ are taken together toform a 5-, 6-, 7-, or 8-membered heterocyclic ring. In anotherembodiment is a compound of Formula (IIC) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ are taken together toform a 5-membered heterocyclic ring. In another embodiment is a compoundof Formula (IIC) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁and R₁₂ are taken together to form a 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (IIC) wherein R₆ is

and J is C(H). In another embodiment is a compound of Formula (IIC)wherein R₆ is

J is C(H), p is 1, and q is 1. In another embodiment is a compound ofFormula (IIC) wherein R₆ is

J is C(H), p is 2, and q is 1. In another embodiment is a compound ofFormula (IIC) wherein R₆ is

J is C(H), p is 3, and q is 1. In another embodiment is a compound ofFormula (IIC) wherein R₆ is

J is C(H), p is 2, and q is 2. In another embodiment is a compound ofFormula (IIC) wherein R₆ is

J is C(H), p is 1, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIC) whereinR₆ is

J is C(H), p is 2, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIC) whereinR₆ is

J is C(H), p is 3, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIC) whereinR₆ is

J is C(H), p is 2, q is 2, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl.

In another embodiment is a compound of Formula (IIC) wherein R₅ ishalogen. In another embodiment is a compound of Formula (IIC) wherein R₅is —CF₃. In another embodiment is a compound of Formula (IIC) wherein R₅is substituted or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (IIC) wherein R₅ is —CH₃. In another embodiment is acompound of Formula (IIC) wherein R₅ is —CH₂CH₃. In another embodimentis a compound of Formula (IIC) wherein R₅ is substituted orunsubstituted C₁-C₆heteroalkyl. In another embodiment is a compound ofFormula (IIC) wherein R₅ is substituted or unsubstitutedC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(IIC) wherein R₅ is substituted or unsubstituted C₃-C₈cycloalkyl. Inanother embodiment is a compound of Formula (IIC) wherein R₅ issubstituted or unsubstituted C₆-C₁₀aryl. In another embodiment is acompound of Formula (IIC) wherein R₅ is substituted or unsubstitutedC₂-C₇heteroaryl.

In another embodiment is a compound of Formula (IIC) wherein R₂ and R₃are each independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(IIC) wherein R₂ and R₃ are each H.

In another embodiment is a compound of Formula (IIC) wherein R₂ and R₃are each independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl; and at least one of R₂ and R₃ is not H. Inanother embodiment is a compound of Formula (IIC) wherein R₂ is H, andR₃ is C₁-C₄alkyl. In another embodiment is a compound of Formula (IIC)wherein R₂ is H, and R₃ is CH₃. In another embodiment is a compound ofFormula (IIC) wherein R₂ is H, and R₃ is C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (IIC) wherein R₂ is H, and R₃ iscyclopropyl. In another embodiment is a compound of Formula (IIC)wherein R₂ is H, and R₃ is cyclopentyl. In another embodiment is acompound of Formula (IIC) wherein R₂ is CH₃, and R₃ is CH₃. In anotherembodiment is a compound of Formula (IIC) wherein R₂ is C₁-C₄alkyl, andR₃ is H. In another embodiment is a compound of Formula (IIC) wherein R₂is CH₃, and R₃ is H. In another embodiment is a compound of Formula(IIC) wherein R₂ is C₃-C₆cycloalkyl, and R₃ is H. In another embodimentis a compound of Formula (IIC) wherein R₂ is cyclopropyl, and R₃ is H.In another embodiment is a compound of Formula (IIC) wherein R₂ iscyclopentyl, and R₃ is H.

In another embodiment is a compound of Formula (IIC) wherein R₂ and R₃are taken together to form a 5- or 6-membered heterocyclic ring. Inanother embodiment is a compound of Formula (IIC) wherein R₂ and R₃ aretaken together to form a 5-membered heterocyclic ring. In anotherembodiment is a compound of Formula (IIC) wherein R₂ and R₃ are takentogether to form 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (IIC) wherein n is 0.

In another embodiment is a compound of Formula (IIC) wherein each R₁ isindependently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,—SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉, —C(═O)R₉,—CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (IIC) wherein each R₁ is independently halogen, —CN, —OH, —CF₃,substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment is a compound of Formula (IIC)wherein each R₁ is independently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H,—CF₃, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkoxy, substituted or unsubstitutedC₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl,substituted or unsubstituted C₃-C₈cycloalkyl, substituted orunsubstituted C₆-C₁₀aryl, or substituted or unsubstitutedC₂-C₇heteroaryl. In another embodiment is a compound of Formula (IIC)wherein each R₁ is independently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H,—CF₃, substituted or unsubstituted C₁-C₆alkyl, or substituted orunsubstituted C₁-C₆alkoxy. In another embodiment is a compound ofFormula (IIC) wherein each R₁ is independently halogen, —CN, —OCF₃,—OCH₂F, —OCF₂H, —CF₃, substituted or unsubstituted C₁-C₆alkyl, orsubstituted or unsubstituted C₁-C₆alkoxy, and n is 3. In anotherembodiment is a compound of Formula (IIC) wherein each R₁ isindependently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H, —CF₃, substituted orunsubstituted C₁-C₆alkyl, or substituted or unsubstituted C₁-C₆alkoxy,and n is 2. In another embodiment is a compound of Formula (IIC) whereinn is 3, and each R₁ is independently halogen. In another embodiment is acompound of Formula (IIC) wherein n is 2, and each R₁ is independentlyhalogen. In another embodiment is a compound of Formula (IIC) wherein nis 2, and each R₁ is independently F or Cl. In another embodiment is acompound of Formula (IIC) wherein n is 2, and each R₁ is F. In anotherembodiment is a compound of Formula (IIC) wherein n is 2, and each R₁ isindependently Cl. In another embodiment is a compound of Formula (IIC)wherein n is 2, and each R₁ is independently halogen or —CF₃. In anotherembodiment is a compound of Formula (IIC) wherein n is 2, and each R₁ isindependently F or —CF₃. In another embodiment is a compound of Formula(IIC) wherein n is 2, and each R₁ is independently Cl or —CF₃. Inanother embodiment is a compound of Formula (IIC) wherein n is 1, and R₁is halogen. In another embodiment is a compound of Formula (IIC) whereinn is 1, and R₁ is F. In another embodiment is a compound of Formula(IIC) wherein n is 1, and R₁ is Cl. In another embodiment is a compoundof Formula (IIC) wherein n is 1, and R₁ is —CF₃. In another embodimentis a compound of Formula (IIC) wherein n is 1, and R₁ is substituted orunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIC) wherein n is 1, and R₁ is CH₃. In another embodiment is a compoundof Formula (IIC) wherein n is 1, and R₁ is substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment is a compound of Formula (IIC)wherein n is 1, and R₁ is —OCH₃. In another embodiment is a compound ofFormula (IIC) wherein n is 1, and R₁ is —OCF₃. In another embodiment isa compound of Formula (IIC) wherein n is 1, and R₁ is —OCF₂H.

In another embodiment, described herein is a compound of Formula (IID):

wherein:

-   -   A is a bond;    -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl;    -   or two R₁ are taken together to form a substituted or        unsubstituted heterocyclic ring or a substituted or        unsubstituted carbocyclic ring;    -   R₂ and R₃ are each independently H, —CN, C₁-C₄alkyl,        C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ are        taken together to form a 5- or 6-membered heterocyclic ring;    -   R₄ is H, halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —SR₈,        —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉, —C(═O)R₉,        —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted        or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl; or        two R₁ are taken together to form a substituted or unsubstituted        heterocyclic ring or a substituted or unsubstituted carbocyclic        ring; wherein when n is 0, R₄ is not halogen;    -   R₅ is halogen, —CN, —OH, —CF₃, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   R₆ is substituted or unsubstituted C₂-C₇heterocycloalkyl;    -   R₁₁ and R₁₂ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or R₁₁ and R₁₂ are taken together to        form a 5-, 6-, 7-, or 8-membered heterocyclic ring;    -   J is C(H);    -   R₁₃ is H, substituted or unsubstituted C₁-C₆alkyl, substituted        or unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        —C₁-C₄alkylC₆-C₁₀aryl, or substituted or unsubstituted        —C₁-C₄alkylC₂-C₇heteroaryl;    -   each R₁₄ and R₁₅ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or    -   R₁₄ and R₁₅ are taken together to form a 4-, 5-, 6-membered        cycloalkyl ring;    -   R₂₁ is halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,        —SR₂₂, —N(R₂₂)S(═O)₂R₂₃, —S(═O)₂N(R₂₂)₂, —S(═O)R₂₃, —S(═O)₂R₂₃,        —C(═O)R₂₃, —CO₂R₂₂, —C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted        or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   each R₂₂ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₂₃ is substituted or unsubstituted C₁-C₆alkyl;    -   each R₈ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₉ is substituted or unsubstituted C₁-C₆alkyl;    -   m is 2-6;    -   n is 0-4;    -   p is 1-3;    -   q is 1-3; or

a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In one embodiment is a compound of Formula (IID) wherein R₆ isunsubstituted C₂-C₇heterocycloalkyl. In another embodiment is a compoundof Formula (IID) wherein R₆ is substituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (IID) wherein R₆ issubstituted or unsubstituted morpholinyl. In another embodiment is acompound of Formula (IID) wherein R₆ is substituted or unsubstitutedpiperazinyl. In another embodiment is a compound of Formula (IID)wherein R₆ is substituted or unsubstituted piperidinyl.

In another embodiment is a compound of Formula (IID) wherein R₅ ishalogen. In another embodiment is a compound of Formula (IID) wherein R₅is —CF₃. In another embodiment is a compound of Formula (IID) wherein R₅is substituted or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (IID) wherein R₅ is —CH₃. In another embodiment is acompound of Formula (IID) wherein R₅ is —CH₂CH₃. In another embodimentis a compound of Formula (IID) wherein R₅ is substituted orunsubstituted C₁-C₆heteroalkyl. In another embodiment is a compound ofFormula (IID) wherein R₅ is substituted or unsubstitutedC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(IID) wherein R₅ is substituted or unsubstituted C₃-C₈cycloalkyl. Inanother embodiment is a compound of Formula (IID) wherein R₅ issubstituted or unsubstituted C₆-C₁₀aryl. In another embodiment is acompound of Formula (IID) wherein R₅ is substituted or unsubstitutedC₂-C₇heteroaryl.

In another embodiment is a compound of Formula (IID) wherein R₂ and R₃are each independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(IID) wherein R₂ and R₃ are each H.

In another embodiment is a compound of Formula (IID) wherein R₂ and R₃are each independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl; and at least one of R₂ and R₃ is not H. Inanother embodiment is a compound of Formula (IID) wherein R₂ is H, andR₃ is C₁-C₄alkyl. In another embodiment is a compound of Formula (IID)wherein R₂ is H, and R₃ is CH₃. In another embodiment is a compound ofFormula (IID) wherein R₂ is H, and R₃ is C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (IID) wherein R₂ is H, and R₃ iscyclopropyl. In another embodiment is a compound of Formula (IID)wherein R₂ is H, and R₃ is cyclopentyl. In another embodiment is acompound of Formula (IID) wherein R₂ is CH₃, and R₃ is CH₃. In anotherembodiment is a compound of Formula (IID) wherein R₂ is C₁-C₄alkyl, andR₃ is H. In another embodiment is a compound of Formula (IID) wherein R₂is CH₃, and R₃ is H. In another embodiment is a compound of Formula(IID) wherein R₂ is C₃-C₆cycloalkyl, and R₃ is H. In another embodimentis a compound of Formula (IID) wherein R₂ is cyclopropyl, and R₃ is H.In another embodiment is a compound of Formula (IID) wherein R₂ iscyclopentyl, and R₃ is H.

In another embodiment is a compound of Formula (IID) wherein R₂ and R₃are taken together to form a 5- or 6-membered heterocyclic ring. Inanother embodiment is a compound of Formula (IID) wherein R₂ and R₃ aretaken together to form a 5-membered heterocyclic ring. In anotherembodiment is a compound of Formula (IID) wherein R₂ and R₃ are takentogether to form 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (IID) wherein n is 0.

In another embodiment is a compound of Formula (IID) wherein each R₁ isindependently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,—SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉, —C(═O)R₉,—CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (IID) wherein each R₁ is independently halogen, —CN, —OH, —CF₃,substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment is a compound of Formula (IID)wherein each R₁ is independently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H,—CF₃, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkoxy, substituted or unsubstitutedC₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl,substituted or unsubstituted C₃-C₈cycloalkyl, substituted orunsubstituted C₆-C₁₀aryl, or substituted or unsubstitutedC₂-C₇heteroaryl. In another embodiment is a compound of Formula (IID)wherein each R₁ is independently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H,—CF₃, substituted or unsubstituted C₁-C₆alkyl, or substituted orunsubstituted C₁-C₆alkoxy. In another embodiment is a compound ofFormula (IID) wherein each R₁ is independently halogen, —CN, —OCF₃,—OCH₂F, —OCF₂H, —CF₃, substituted or unsubstituted C₁-C₆alkyl, orsubstituted or unsubstituted C₁-C₆alkoxy, and n is 3. In anotherembodiment is a compound of Formula (IID) wherein each R₁ isindependently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H, —CF₃, substituted orunsubstituted C₁-C₆alkyl, or substituted or unsubstituted C₁-C₆alkoxy,and n is 2. In another embodiment is a compound of Formula (IID) whereinn is 3, and each R₁ is independently halogen. In another embodiment is acompound of Formula (IID) wherein n is 2, and each R₁ is independentlyhalogen. In another embodiment is a compound of Formula (IID) wherein nis 2, and each R₁ is independently F or Cl. In another embodiment is acompound of Formula (IID) wherein n is 2, and each R₁ is F. In anotherembodiment is a compound of Formula (IID) wherein n is 2, and each R₁ isindependently Cl. In another embodiment is a compound of Formula (IID)wherein n is 2, and each R₁ is independently halogen or —CF₃. In anotherembodiment is a compound of Formula (IID) wherein n is 2, and each R₁ isindependently F or —CF₃. In another embodiment is a compound of Formula(IID) wherein n is 2, and each R₁ is independently Cl or —CF₃. Inanother embodiment is a compound of Formula (IID) wherein n is 1, and R₁is halogen. In another embodiment is a compound of Formula (IID) whereinn is 1, and R₁ is F. In another embodiment is a compound of Formula(IID) wherein n is 1, and R₁ is Cl. In another embodiment is a compoundof Formula (IID) wherein n is 1, and R₁ is —CF₃. In another embodimentis a compound of Formula (IID) wherein n is 1, and R₁ is substituted orunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IID) wherein n is 1, and R₁ is CH₃. In another embodiment is a compoundof Formula (IID) wherein n is 1, and R₁ is substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment is a compound of Formula (IID)wherein n is 1, and R₁ is —OCH₃. In another embodiment is a compound ofFormula (IID) wherein n is 1, and R₁ is —OCF₃. In another embodiment isa compound of Formula (IID) wherein n is 1, and R₁ is —OCF₂H.

In another embodiment is a compound of Formula (IID) wherein R₄ is H,halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —SR₈, —N(R₈)S(═O)₂R₉,—S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂,—C(═O)N(R₈)₂, —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl, orsubstituted or unsubstituted C₁-C₆alkoxy. In another embodiment is acompound of Formula (IID) wherein R₄ is H, halogen, —CN, —OH, —OCF₃,substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment is a compound of Formula (IID)wherein R₄ is H. In another embodiment is a compound of Formula (IID)wherein R₄ is halogen. In another embodiment is a compound of Formula(IID) wherein R₄ is F. In another embodiment is a compound of Formula(IID) wherein R₄ is Cl. In another embodiment is a compound of Formula(IID) wherein R₄ is Br. In another embodiment is a compound of Formula(IID) wherein R₄ is —CF₃. In another embodiment is a compound of Formula(IID) wherein R₄ is —OCF₃. In another embodiment is a compound ofFormula (IID) R₄ is —CH₃. In another embodiment is a compound of Formula(IID) wherein R₄ is —OCH₃.

In another embodiment is a compound of Formula (IID) wherein n is 0 andR₄ is H. In another embodiment is a compound of Formula (IID) wherein nis 0 and R₄ is halogen. In another embodiment is a compound of Formula(IID) wherein n is 0 and R₄ is F. In another embodiment is a compound ofFormula (IID) wherein n is 0 and R₄ is Cl. In another embodiment is acompound of Formula (IID) wherein n is 0 and R₄ is Br. In anotherembodiment is a compound of Formula (IID) wherein n is 0 and R₄ is —CF₃.In another embodiment is a compound of Formula (IID) wherein n is 0 andR₄ is —OCF₃. In another embodiment is a compound of Formula (IID)wherein n is 0 and R₄ is —CH₃. In another embodiment is a compound ofFormula (IID) wherein n is 0 and R₄ is —OCH₃.

In another embodiment is a compound of Formula (IID) wherein n is 1, R₁is Cl, and R₄ is Cl. In another embodiment is a compound of Formula(IID) wherein n is 1, R₁ is —CH₃, and R₄ is Cl. In another embodiment isa compound of Formula (IID) wherein n is 1, R₁ is —OCH₃, and R₄ is Cl.In another embodiment is a compound of Formula (IID) wherein n is 1, R₁is —CF₃, and R₄ is Cl. In another embodiment is a compound of Formula(IID) wherein n is 1, R₁ is —OCF₃, and R₄ is Cl. In another embodimentis a compound of Formula (IID) wherein n is 1, R₁ is Cl, and R₄ is F. Inanother embodiment is a compound of Formula (IID) wherein n is 1, R₁ is—CH₃, and R₄ is F. In another embodiment is a compound of Formula (IID)wherein n is 1, R₁ is —OCH₃, and R₄ is F. In another embodiment is acompound of Formula (IID) wherein n is 1, R₁ is —CF₃, and R₄ is F. Inanother embodiment is a compound of Formula (IID) wherein n is 1, R₁ is—OCF₃, and R₄ is F. In another embodiment is a compound of Formula (IID)wherein n is 1, R₁ is Cl, and R₄ is H. In another embodiment is acompound of Formula (IID) wherein n is 1, R₁ is —CH₃, and R₄ is H. Inanother embodiment is a compound of Formula (IID) wherein n is 1, R₁ is—OCH₃, and R₄ is H. In another embodiment is a compound of Formula (IID)wherein n is 1, R₁ is —CF₃, and R₄ is H. In another embodiment is acompound of Formula (IID) wherein n is 1, R₁ is —OCF₃, and R₄ is H. Inanother embodiment is a compound of Formula (IID) wherein n is 1, R₁ isCl, and R₄ is —OCH₃. In another embodiment is a compound of Formula(IID) wherein n is 1, R₁ is —CH₃, and R₄ is —OCH₃. In another embodimentis a compound of Formula (IID) wherein n is 1, R₁ is —OCH₃, and R₄ is—OCH₃. In another embodiment is a compound of Formula (IID) wherein n is1, R₁ is —CF₃, and R₄ is —OCH₃. In another embodiment is a compound ofFormula (IID) wherein n is 1, R₁ is —OCF₃, and R₄ is —OCH₃. In anotherembodiment is a compound of Formula (IID) wherein n is 1, R₁ is Cl, andR₄ is —OCF₃. In another embodiment is a compound of Formula (IID)wherein n is 1, R₁ is —CH₃, and R₄ is —OCF₃. In another embodiment is acompound of Formula (IID) wherein n is 1, R₁ is —OCH₃, and R₄ is —OCF₃.In another embodiment is a compound of Formula (IID) wherein n is 1, R₁is —CF₃, and R₄ is —OCF₃. In another embodiment is a compound of Formula(IID) wherein n is 1, R₁ is —OCF₃, and R₄ is —OCF₃.

In another embodiment, described herein is a compound of Formula (IID′):

wherein:

-   -   A is a bond;    -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl;    -   or two R₁ are taken together to form a substituted or        unsubstituted heterocyclic ring or a substituted or        unsubstituted carbocyclic ring;    -   R₂ and R₃ are each independently H, —CN, C₁-C₄alkyl,        C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ are        taken together to form a 5- or 6-membered heterocyclic ring;    -   R₄ is H, F, Cl, Br, I, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H,        —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉,        —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉,        substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆alkoxy, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl; or two R₁ are        taken together to form a substituted or unsubstituted        heterocyclic ring or a substituted or unsubstituted carbocyclic        ring; wherein when n is 0, R₄ is not Cl;    -   R₅ is halogen, —CN, —OH, —CF₃, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   R₆ is substituted or unsubstituted C₂-C₇heterocycloalkyl;    -   R₁₁ and R₁₂ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or R₁₁ and R₁₂ are taken together to        form a 5-, 6-, 7-, or 8-membered heterocyclic ring;    -   J is C(H);    -   R₁₃ is H, substituted or unsubstituted C₁-C₆alkyl, substituted        or unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        —C₁-C₄alkylC₆-C₁₀aryl, or substituted or unsubstituted        —C₁-C₄alkylC₂-C₇heteroaryl;    -   each R₁₄ and R₁₅ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or    -   R₁₄ and R₁₅ are taken together to form a 4-, 5-, 6-membered        cycloalkyl ring;    -   R₂₁ is halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,        —SR₂₂, —N(R₂₂)S(═O)₂R₂₃, —S(═O)₂N(R₂₂)₂, —S(═O)R₂₃, —S(═O)₂R₂₃,        —C(═O)R₂₃, —CO₂R₂₂, —C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted        or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   each R₂₂ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₂₃ is substituted or unsubstituted C₁-C₆alkyl;    -   each R₈ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₉ is substituted or unsubstituted C₁-C₆alkyl;    -   m is 2-6;    -   n is 0-4;    -   p is 1-3;    -   q is 1-3; or

a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another aspect, described herein is a compound of Formula (III):

wherein:

-   -   A is a bond, O, or N(R₁₀);    -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl;    -   or two R₁ are taken together to form a substituted or        unsubstituted heterocyclic ring or a substituted or        unsubstituted carbocyclic ring;    -   R₂ and R₃ are each independently H, —CN, C₁-C₄alkyl,        C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ are        taken together to form a 5- or 6-membered heterocyclic ring;    -   R₅ is halogen, —CN, —OH, —CF₃, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   R₆ is substituted or unsubstituted C₂-C₇heterocycloalkyl,        substituted or unsubstituted C₃-C₈cycloalkyl, substituted or        unsubstituted C₂-C₇heteroaryl, —(C(R₁₄)(R₁₅))_(m)R₂₁,        —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), or

-   -   R₁₁ and R₁₂ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or R₁₁ and R₁₂ are taken together to        form a 5-, 6-, 7-, or 8-membered heterocyclic ring;    -   J is C(H), or N;    -   R₁₃ is H, substituted or unsubstituted C₁-C₆alkyl, substituted        or unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        —C₁-C₄alkylC₆-C₁₀aryl, or substituted or unsubstituted        —C₁-C₄alkyC₂-C₇heteroaryl;    -   each R₁₄ and R₁₅ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or    -   R₁₄ and R₁₅ are taken together to form a 4-, 5-, 6-membered        cycloalkyl ring;    -   R₂₁ is halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,        —SR₂₂, —N(R₂₂)S(═O)₂R₂₃, —S(═O)₂N(R₂₂)₂, —S(═O)R₂₃, —S(═O)₂R₂₃,        —C(═O)R₂₃, —CO₂R₂₂, —C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted        or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   each R₂₂ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₂₃ is substituted or unsubstituted C₁-C₆alkyl;    -   each R₈ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₉ is substituted or unsubstituted C₁-C₆alkyl;    -   R₁₀ is H, or C₁-C₄alkyl;    -   m is 2-6;    -   n is 0-5;    -   p is 1-3;    -   q is 1-3; or

a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment is a compound of Formula (III) wherein A is O, orN(R₁₀). In another embodiment is a compound of Formula (III) wherein Ais O, CH₂, or N(H). In another embodiment is a compound of Formula (III)wherein A is O. In another embodiment is a compound of Formula (III)wherein A is N(R₁₀). In another embodiment is a compound of Formula(III) wherein A is N(H). In another embodiment is a compound of Formula(III) wherein A is N(CH₃). In another embodiment is a compound ofFormula (III) wherein A is a bond.

In another embodiment is a compound of Formula (III) wherein R₆ issubstituted or unsubstituted C₃-C₈cycloalkyl. In another embodiment is acompound of Formula (III) wherein R₆ is substituted or unsubstitutedcyclopropyl. In another embodiment is a compound of Formula (III)wherein R₆ is substituted or unsubstituted cyclobutyl. In anotherembodiment is a compound of Formula (III) wherein R₆ is substituted orunsubstituted cyclopentyl. In another embodiment is a compound ofFormula (III) wherein R₆ is substituted or unsubstituted cyclohexyl.

In another embodiment is a compound of Formula (III) wherein R₆ issubstituted or unsubstituted C₂-C₇heteroaryl. In another embodiment is acompound of Formula (III) wherein R₆ is substituted or unsubstitutedfuranyl, thiophenyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl,isoxazolyl, isothiazolyl, pyrazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, indolyl,benzothiophenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, pyrazolopyridinyl,imidazopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, indolizinyl,purinyl, furopyridinyl, thienopyridinyl, furopyrrolyl, furofuranyl,thienofuranyl, 1,4-dihydropyrrolopyrrolyl, thienopyrrolyl,thienothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl,furopyrazolyl, thienopyrazolyl, selenophenyl, selenazolyl, andbenzoisoxazolyl. In another embodiment is a compound of Formula (III)wherein R₆ is substituted or unsubstituted pyridyl. In anotherembodiment is a compound of Formula (III) wherein R₆ is substitutedpyridyl. In another embodiment is a compound of Formula (III) wherein R₆is unsubstituted pyridyl.

In another embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁. In another embodiment is a compound of Formula(III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₂₁, and each R₁₄ and R₁₅ are H.In another embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁, m is 2, and each R₁₄ and R₁₅ are H. In anotherembodiment is a compound of Formula (III) wherein R₆ is —(CH₂)_(m)R₂₁, mis 2, and R₂₁ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (III) wherein R₆ is—(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted or unsubstitutedC₃-C₈cycloalkyl. In another embodiment is a compound of Formula (III)wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted orunsubstituted C₆-C₁₀aryl. In another embodiment is a compound of Formula(III) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted orunsubstituted phenyl. In another embodiment is a compound of Formula(III) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted orunsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (III) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is —OH.

In another embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁, m is 3, and each R₁₄ and R₁₅ are H. In anotherembodiment is a compound of Formula (III) wherein R₆ is —(CH₂)_(m)R₂₁, mis 3, and R₂₁ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (III) wherein R₆ is—(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted or unsubstitutedC₃-C₈cycloalkyl. In another embodiment is a compound of Formula (III)wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted orunsubstituted C₆-C₁₀aryl. In another embodiment is a compound of Formula(III) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted orunsubstituted phenyl. In another embodiment is a compound of Formula(III) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted orunsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (III) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is —OH.

In another embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂). In another embodiment is a compound ofFormula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), m is 2, andeach R₁₄ and R₁₅ are H. In another embodiment is a compound of Formula(III) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ areeach H. In another embodiment is a compound of Formula (III) wherein R₆is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is H. In another embodiment is a compound of Formula(III) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is CH₃, and R₁₂is H. In another embodiment is a compound of Formula (III) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is substituted or unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (III) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is CH₃, and R₁₂ is CH₃. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ are taken together toform a 5-, 6-, 7-, or 8-membered heterocyclic ring. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ are taken together toform a 5-membered heterocyclic ring. In another embodiment is a compoundof Formula (III) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁and R₁₂ are taken together to form a 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (III) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂). In another embodiment is a compound ofFormula (III) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), m is 3, andeach R₁₄ and R₁₅ are H. In another embodiment is a compound of Formula(III) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ areeach H. In another embodiment is a compound of Formula (III) wherein R₆is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is H. In another embodiment is a compound of Formula(III) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is CH₃, and R₁₂is H. In another embodiment is a compound of Formula (III) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is substituted or unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (III) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is CH₃, and R₁₂ is CH₃. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ are taken together toform a 5-, 6-, 7-, or 8-membered heterocyclic ring. In anotherembodiment is a compound of Formula (III) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ are taken together toform a 5-membered heterocyclic ring. In another embodiment is a compoundof Formula (III) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁and R₁₂ are taken together to form a 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (III) wherein R₆ issubstituted or unsubstituted C₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (III) wherein R₆ is

In another embodiment is a compound of Formula (III) wherein R₆ is

and J is C(H). In another embodiment is a compound of Formula (III)wherein R₆ is

J is C(H), p is 1, and q is 1. In another embodiment is a compound ofFormula (III) wherein R₆ is

J is C(H), p is 2, and q is 1. In another embodiment is a compound ofFormula (III) wherein R₆ is

J is C(H), p is 3, and q is 1. In another embodiment is a compound ofFormula (III) wherein R₆ is

J is C(H), p is 2, and q is 2. In another embodiment is a compound ofFormula (III) wherein R₆ is

J is C(H), p is 1, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (III) whereinR₆ is

J is C(H), p is 2, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (III) whereinR₆ is

J is C(H), p is 3, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (III) whereinR₆ is

J is C(H), p is 2, q is 2, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl.

In another embodiment is a compound of Formula (III) wherein R₆ is

and J is N. In another embodiment is a compound of Formula (III) whereinR₆ is

J is N, p is 2, and q is 2. In another embodiment is a compound ofFormula (III) wherein R₆ is

J is N, p is 2, q is 2, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl.

In another embodiment is a compound of Formula (III) wherein R₈ ishalogen. In another embodiment is a compound of Formula (III) wherein R₈is —CF₃. In another embodiment is a compound of Formula (III) wherein R₈is substituted or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (III) wherein R₈ is —CH₃. In another embodiment is acompound of Formula (III) wherein R₈ is —CH₂CH₃. In another embodimentis a compound of Formula (III) wherein R₈ is substituted orunsubstituted C₁-C₆heteroalkyl. In another embodiment is a compound ofFormula (III) wherein R₈ is substituted or unsubstitutedC₃-C₈cycloalkyl. In another embodiment is a compound of Formula (III)wherein R₈ is substituted or unsubstituted C₆-C₁₀aryl. In anotherembodiment is a compound of Formula (III) wherein R₈ is substituted orunsubstituted C₂-C₇heteroaryl.

In another embodiment is a compound of Formula (III) wherein R₂ and R₃are each independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(III) wherein R₂ and R₃ are each H.

In another embodiment is a compound of Formula (III) wherein R₂ and R₃are each independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl; and at least one of R₂ and R₃ is not H. Inanother embodiment is a compound of Formula (III) wherein R₂ is H, andR₃ is C₁-C₄alkyl. In another embodiment is a compound of Formula (III)wherein R₂ is H, and R₃ is CH₃. In another embodiment is a compound ofFormula (III) wherein R₂ is H, and R₃ is C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (III) wherein R₂ is H, and R₃ iscyclopropyl. In another embodiment is a compound of Formula (III)wherein R₂ is H, and R₃ is cyclopentyl. In another embodiment is acompound of Formula (III) wherein R₂ is CH₃, and R₃ is CH₃. In anotherembodiment is a compound of Formula (III) wherein R₂ is C₁-C₄alkyl, andR₃ is H. In another embodiment is a compound of Formula (III) wherein R₂is CH₃, and R₃ is H. In another embodiment is a compound of Formula(III) wherein R₂ is C₃-C₆cycloalkyl, and R₃ is H. In another embodimentis a compound of Formula (III) wherein R₂ is cyclopropyl, and R₃ is H.In another embodiment is a compound of Formula (III) wherein R₂ iscyclopentyl, and R₃ is H.

In another embodiment is a compound of Formula (III) wherein R₂ and R₃are taken together to form a 5- or 6-membered heterocyclic ring. Inanother embodiment is a compound of Formula (III) wherein R₂ and R₃ aretaken together to form a 5-membered heterocyclic ring. In anotherembodiment is a compound of Formula (III) wherein R₂ and R₃ are takentogether to form 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (III) wherein n is 0.

In another embodiment is a compound of Formula (III) wherein each R₁ isindependently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,—SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉, —C(═O)R₉,—CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (III) wherein each R₁ is independently halogen, —CN, —OH, —CF₃,substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment is a compound of Formula (III)wherein each R₁ is independently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H,—CF₃, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkoxy, substituted or unsubstitutedC₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl,substituted or unsubstituted C₃-C₈cycloalkyl, substituted orunsubstituted C₆-C₁₀aryl, or substituted or unsubstitutedC₂-C₇heteroaryl. In another embodiment is a compound of Formula (III)wherein each R₁ is independently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H,—CF₃, substituted or unsubstituted C₁-C₆alkyl, or substituted orunsubstituted C₁-C₆alkoxy. In another embodiment is a compound ofFormula (III) wherein each R₁ is independently halogen, —CN, —OCF₃,—OCH₂F, —OCF₂H, —CF₃, substituted or unsubstituted C₁-C₆alkyl, orsubstituted or unsubstituted C₁-C₆alkoxy, and n is 3. In anotherembodiment is a compound of Formula (III) wherein each R₁ isindependently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H, —CF₃, substituted orunsubstituted C₁-C₆alkyl, or substituted or unsubstituted C₁-C₆alkoxy,and n is 2. In another embodiment is a compound of Formula (III) whereinn is 3, and each R₁ is independently halogen. In another embodiment is acompound of Formula (III) wherein n is 2, and each R₁ is independentlyhalogen. In another embodiment is a compound of Formula (III) wherein nis 2, and each R₁ is independently F or Cl. In another embodiment is acompound of Formula (III) wherein n is 2, and each R₁ is F. In anotherembodiment is a compound of Formula (III) wherein n is 2, and each R₁ isindependently Cl. In another embodiment is a compound of Formula (III)wherein n is 2, and each R₁ is independently halogen or —CF₃. In anotherembodiment is a compound of Formula (III) wherein n is 2, and each R₁ isindependently F or —CF₃. In another embodiment is a compound of Formula(III) wherein n is 2, and each R₁ is independently Cl or —CF₃. Inanother embodiment is a compound of Formula (III) wherein n is 1, and R₁is halogen. In another embodiment is a compound of Formula (III) whereinn is 1, and R₁ is F. In another embodiment is a compound of Formula(III) wherein n is 1, and R₁ is Cl. In another embodiment is a compoundof Formula (III) wherein n is 1, and R₁ is —CF₃. In another embodimentis a compound of Formula (III) wherein n is 1, and R₁ is substituted orunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(III) wherein n is 1, and R₁ is CH₃. In another embodiment is a compoundof Formula (III) wherein n is 1, and R₁ is substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment is a compound of Formula (III)wherein n is 1, and R₁ is —OCH₃. In another embodiment is a compound ofFormula (III) wherein n is 1, and R₁ is —OCF₃. In another embodiment isa compound of Formula (III) wherein n is 1, and R₁ is —OCF₂H.

In another aspect, described herein is a compound of Formula (IV):

wherein:

-   -   A is a bond, O, or N(R₁₀);    -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl;    -   or two R₁ are taken together to form a substituted or        unsubstituted heterocyclic ring or a substituted or        unsubstituted carbocyclic ring;    -   R₂ and R₃ are each independently H, —CN, C₁-C₄alkyl,        C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ are        taken together to form a 5- or 6-membered heterocyclic ring;    -   R₅ is halogen, —CN, —OH, —CF₃, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   R₆ is substituted or unsubstituted C₂-C₇heterocycloalkyl,        substituted or unsubstituted C₃-C₈cycloalkyl, substituted or        unsubstituted C₂-C₇heteroaryl, —(C(R₁₄)(R₁₅))_(m)R₂₁,        —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), or

-   -   R₁₁ and R₁₂ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or R₁₁ and R₁₂ are taken together to        form a 5-, 6-, 7-, or 8-membered heterocyclic ring;    -   J is C(H), or N;    -   R₁₃ is H, substituted or unsubstituted C₁-C₆alkyl, substituted        or unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        —C₁-C₄alkylC₆-C₁₀aryl, or substituted or unsubstituted        —C₁-C₄alkyC₂-C₇heteroaryl;    -   each R₁₄ and R₁₅ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or    -   R₁₄ and R₁₅ are taken together to form a 4-, 5-, 6-membered        cycloalkyl ring;    -   R₂₁ is halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,        —SR₂₂, —N(R₂₂)S(═O)₂R₂₃, —S(═O)₂N(R₂₂)₂, —S(═O)R₂₃, —S(═O)₂R₂₃,        —C(═O)R₂₃, —CO₂R₂₂, —C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted        or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   each R₂₂ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₂₃ is substituted or unsubstituted C₁-C₆alkyl;    -   each R₈ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₉ is substituted or unsubstituted C₁-C₆ alkyl;    -   R₁₀ is H, or C₁-C₄alkyl;    -   m is 2-6;    -   n is 0-5;    -   p is 1-3;    -   q is 1-3; or

a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment is a compound of Formula (IV) wherein A is O, orN(R₁₀). In another embodiment is a compound of Formula (IV) wherein A isO, or N(H). In another embodiment is a compound of Formula (IV) whereinA is O. In another embodiment is a compound of Formula (IV) wherein A isN(R₁₀). In another embodiment is a compound of Formula (IV) wherein A isN(H). In another embodiment is a compound of Formula (IV) wherein A isN(CH₃). In another embodiment is a compound of Formula (IV) wherein A isa bond.

In another embodiment is a compound of Formula (IV) wherein R₆ issubstituted or unsubstituted C₃-C₈cycloalkyl. In another embodiment is acompound of Formula (IV) wherein R₆ is substituted or unsubstitutedcyclopropyl. In another embodiment is a compound of Formula (IV) whereinR₆ is substituted or unsubstituted cyclobutyl. In another embodiment isa compound of Formula (IV) wherein R₆ is substituted or unsubstitutedcyclopentyl. In another embodiment is a compound of Formula (IV) whereinR₆ is substituted or unsubstituted cyclohexyl.

In another embodiment is a compound of Formula (IV) wherein R₆ issubstituted or unsubstituted C₂-C₇heteroaryl. In another embodiment is acompound of Formula (IV) wherein R₆ is substituted or unsubstitutedfuranyl, thiophenyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl,isoxazolyl, isothiazolyl, pyrazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, indolyl,benzothiophenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, pyrazolopyridinyl,imidazopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, indolizinyl,purinyl, furopyridinyl, thienopyridinyl, furopyrrolyl, furofuranyl,thienofuranyl, 1,4-dihydropyrrolopyrrolyl, thienopyrrolyl,thienothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl,furopyrazolyl, thienopyrazolyl, selenophenyl, selenazolyl, andbenzoisoxazolyl. In another embodiment is a compound of Formula (IV)wherein R₆ is substituted or unsubstituted pyridyl. In anotherembodiment is a compound of Formula (IV) wherein R₆ is substitutedpyridyl. In another embodiment is a compound of Formula (IV) wherein R₆is unsubstituted pyridyl.

In another embodiment is a compound of Formula (IV) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁. In another embodiment is a compound of Formula(IV) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₂₁, and each R₁₄ and R₁₅ are H. Inanother embodiment is a compound of Formula (IV) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁, m is 2, and each R₁₄ and R₁₅ are H. In anotherembodiment is a compound of Formula (IV) wherein R₆ is —(CH₂)_(m)R₂₁, mis 2, and R₂₁ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (IV) wherein R₆ is—(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted or unsubstitutedC₃-C₈cycloalkyl. In another embodiment is a compound of Formula (IV)wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted orunsubstituted C₆-C₁₀aryl. In another embodiment is a compound of Formula(IV) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted orunsubstituted phenyl. In another embodiment is a compound of Formula(IV) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted orunsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (IV) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is —OH.

In another embodiment is a compound of Formula (IV) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁, m is 3, and each R₁₄ and R₁₅ are H. In anotherembodiment is a compound of Formula (IV) wherein R₆ is —(CH₂)_(m)R₂₁, mis 3, and R₂₁ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (IV) wherein R₆ is—(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted or unsubstitutedC₃-C₈cycloalkyl. In another embodiment is a compound of Formula (IV)wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted orunsubstituted C₆-C₁₀aryl. In another embodiment is a compound of Formula(IV) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted orunsubstituted phenyl. In another embodiment is a compound of Formula(IV) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted orunsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (IV) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is —OH.

In another embodiment is a compound of Formula (IV) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂). In another embodiment is a compound ofFormula (IV) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), m is 2, andeach R₁₄ and R₁₅ are H. In another embodiment is a compound of Formula(IV) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ areeach H. In another embodiment is a compound of Formula (IV) wherein R₆is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is H. In another embodiment is a compound of Formula(IV) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is CH₃, and R₁₂ isH. In another embodiment is a compound of Formula (IV) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is substituted or unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IV) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is CH₃, and R₁₂ is CH₃. In anotherembodiment is a compound of Formula (IV) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ are taken together toform a 5-, 6-, 7-, or 8-membered heterocyclic ring. In anotherembodiment is a compound of Formula (IV) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ are taken together toform a 5-membered heterocyclic ring. In another embodiment is a compoundof Formula (IV) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ andR₁₂ are taken together to form a 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (IV) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂). In another embodiment is a compound ofFormula (IV) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), m is 3, andeach R₁₄ and R₁₅ are H. In another embodiment is a compound of Formula(IV) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ areeach H. In another embodiment is a compound of Formula (IV) wherein R₆is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is H. In another embodiment is a compound of Formula(IV) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is CH₃, and R₁₂ isH. In another embodiment is a compound of Formula (IV) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is substituted or unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IV) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is CH₃, and R₁₂ is CH₃. In anotherembodiment is a compound of Formula (IV) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ are taken together toform a 5-, 6-, 7-, or 8-membered heterocyclic ring. In anotherembodiment is a compound of Formula (IV) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ are taken together toform a 5-membered heterocyclic ring. In another embodiment is a compoundof Formula (IV) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ andR₁₂ are taken together to form a 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (IV) wherein R₆ issubstituted or unsubstituted C₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (IV) wherein R₆ is

In another embodiment is a compound of Formula (IV) wherein R₆ is

and J is C(H). In another embodiment is a compound of Formula (IV)wherein R₆ is

J is C(H), p is 1, and q is 1. In another embodiment is a compound ofFormula (IV) wherein R₆ is

J is C(H), p is 2, and q is 1. In another embodiment is a compound ofFormula (IV) wherein R₆ is

J is C(H), p is 3, and q is 1. In another embodiment is a compound ofFormula (IV) wherein R₆ is

J is C(H), p is 2, and q is 2. In another embodiment is a compound ofFormula (IV) wherein R₆ is

J is C(H), p is 1, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IV) whereinR₆ is

J is C(H), p is 2, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IV) whereinR₆ is

J is C(H), p is 3, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IV) whereinR₆ is

J is C(H), p is 2, q is 2, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl.

In another embodiment is a compound of Formula (IV) wherein R₆ is

and J is N. In another embodiment is a compound of Formula (IV) whereinR₆ is

J is N, p is 2, and q is 2. In another embodiment is a compound ofFormula (IV) wherein R₆ is

J is N, p is 2, q is 2, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl.

In another embodiment is a compound of Formula (IV) wherein R₅ ishalogen. In another embodiment is a compound of Formula (IV) wherein R₅is —CF₃. In another embodiment is a compound of Formula (IV) wherein R₅is substituted or unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (IV) wherein R₅ is —CH₃. In another embodiment is acompound of Formula (IV) wherein R₅ is —CH₂CH₃. In another embodiment isa compound of Formula (IV) wherein R₅ is substituted or unsubstitutedC₁-C₆heteroalkyl. In another embodiment is a compound of Formula (IV)wherein R₅ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (IV) wherein R₅ issubstituted or unsubstituted C₃-C₈cycloalkyl. In another embodiment is acompound of Formula (IV) wherein R₅ is substituted or unsubstitutedC₆-C₁₀aryl. In another embodiment is a compound of Formula (IV) whereinR₅ is substituted or unsubstituted C₂-C₇heteroaryl.

In another embodiment is a compound of Formula (IV) wherein R₂ and R₃are each independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(IV) wherein R₂ and R₃ are each H.

In another embodiment is a compound of Formula (IV) wherein R₂ and R₃are each independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl; and at least one of R₂ and R₃ is not H. Inanother embodiment is a compound of Formula (IV) wherein R₂ is H, and R₃is C₁-C₄alkyl. In another embodiment is a compound of Formula (IV)wherein R₂ is H, and R₃ is CH₃. In another embodiment is a compound ofFormula (IV) wherein R₂ is H, and R₃ is C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (IV) wherein R₂ is H, and R₃ iscyclopropyl. In another embodiment is a compound of Formula (IV) whereinR₂ is H, and R₃ is cyclopentyl. In another embodiment is a compound ofFormula (IV) wherein R₂ is CH₃, and R₃ is CH₃. In another embodiment isa compound of Formula (IV) wherein R₂ is C₁-C₄alkyl, and R₃ is H. Inanother embodiment is a compound of Formula (IV) wherein R₂ is CH₃, andR₃ is H. In another embodiment is a compound of Formula (IV) wherein R₂is C₃-C₆cycloalkyl, and R₃ is H. In another embodiment is a compound ofFormula (IV) wherein R₂ is cyclopropyl, and R₃ is H. In anotherembodiment is a compound of Formula (IV) wherein R₂ is cyclopentyl, andR₃ is H.

In another embodiment is a compound of Formula (IV) wherein R₂ and R₃are taken together to form a 5- or 6-membered heterocyclic ring. Inanother embodiment is a compound of Formula (IV) wherein R₂ and R₃ aretaken together to form a 5-membered heterocyclic ring. In anotherembodiment is a compound of Formula (IV) wherein R₂ and R₃ are takentogether to form 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (IV) wherein n is 0.

In another embodiment is a compound of Formula (IV) wherein each R₁ isindependently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,—SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉, —C(═O)R₉,—CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (IV) wherein each R₁ is independently halogen, —CN, —OH, —CF₃,substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment is a compound of Formula (IV) whereineach R₁ is independently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl, substitutedor unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (IV) wherein each R₁ is independently halogen, —CN, —OCF₃,—OCH₂F, —OCF₂H, —CF₃, substituted or unsubstituted C₁-C₆alkyl, orsubstituted or unsubstituted C₁-C₆alkoxy. In another embodiment is acompound of Formula (IV) wherein each R₁ is independently halogen, —CN,—OCF₃, —OCH₂F, —OCF₂H, —CF₃, substituted or unsubstituted C₁-C₆alkyl, orsubstituted or unsubstituted C₁-C₆alkoxy, and n is 3. In anotherembodiment is a compound of Formula (IV) wherein each R₁ isindependently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H, —CF₃, substituted orunsubstituted C₁-C₆alkyl, or substituted or unsubstituted C₁-C₆alkoxy,and n is 2. In another embodiment is a compound of Formula (IV) whereinn is 3, and each R₁ is independently halogen. In another embodiment is acompound of Formula (IV) wherein n is 2, and each R₁ is independentlyhalogen. In another embodiment is a compound of Formula (IV) wherein nis 2, and each R₁ is independently F or Cl. In another embodiment is acompound of Formula (IV) wherein n is 2, and each R₁ is F. In anotherembodiment is a compound of Formula (IV) wherein n is 2, and each R₁ isindependently Cl. In another embodiment is a compound of Formula (IV)wherein n is 2, and each R₁ is independently halogen or —CF₃. In anotherembodiment is a compound of Formula (IV) wherein n is 2, and each R₁ isindependently F or —CF₃. In another embodiment is a compound of Formula(IV) wherein n is 2, and each R₁ is independently Cl or —CF₃. In anotherembodiment is a compound of Formula (IV) wherein n is 1, and R₁ ishalogen. In another embodiment is a compound of Formula (IV) wherein nis 1, and R₁ is F. In another embodiment is a compound of Formula (IV)wherein n is 1, and R₁ is Cl. In another embodiment is a compound ofFormula (IV) wherein n is 1, and R₁ is —CF₃. In another embodiment is acompound of Formula (IV) wherein n is 1, and R₁ is substituted orunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IV) wherein n is 1, and R₁ is CH₃. In another embodiment is a compoundof Formula (IV) wherein n is 1, and R₁ is substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment is a compound of Formula (IV) whereinn is 1, and R₁ is —OCH₃. In another embodiment is a compound of Formula(IV) wherein n is 1, and R₁ is —OCF₃. In another embodiment is acompound of Formula (IV) wherein n is 1, and R₁ is —OCF₂H.

In another aspect, described herein is a compound of Formula (V):

wherein:

-   -   A is a bond, O, or N(R₁₀);    -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl;    -   or two R₁ are taken together to form a substituted or        unsubstituted heterocyclic ring or a substituted or        unsubstituted carbocyclic ring;    -   R₂ and R₃ are each independently H, —CN, C₁-C₄alkyl,        C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ are        taken together to form a 5- or 6-membered heterocyclic ring;    -   R₅ is halogen, —CN, —OH, —CF₃, unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl;    -   R₆ is substituted or unsubstituted C₂-C₇heterocycloalkyl,        substituted or unsubstituted C₃-C₈cycloalkyl, substituted or        unsubstituted C₂-C₇heteroaryl, —(C(R₁₄)(R₁₅))_(m)R₂₁,        —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), or

-   -   R₁₁ and R₁₂ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or R₁₁ and R₁₂ are taken together to        form a 5-, 6-, 7-, or 8-membered heterocyclic ring;    -   J is C(H), or N;    -   R₁₃ is H, substituted or unsubstituted C₁-C₆alkyl, substituted        or unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        —C₁-C₄alkylC₆-C₁₀aryl, or substituted or unsubstituted        —C₁-C₄alkylC₂-C₇heteroaryl;    -   each R₁₄ and R₁₅ are each independently H, or substituted or        unsubstituted C₁-C₆alkyl; or    -   R₁₄ and R₁₅ are taken together to form a 4-, 5-, 6-membered        cycloalkyl ring;    -   R₂₁ is halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,        —SR₂₂, —N(R₂₂)S(═O)₂R₂₃, —S(═O)₂N(R₂₂)₂, —S(═O)R₂₃, —S(═O)₂R₂₃,        —C(═O)R₂₃, —CO₂R₂₂, —C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted        or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        C₆-C₁₀aryl, or substituted or unsubstituted C₂-C₇heteroaryl;    -   each R₂₂ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₂₃ is substituted or unsubstituted C₁-C₆alkyl;    -   each R₈ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₉ is substituted or unsubstituted C₁-C₆alkyl;    -   R₁₀ is H, or C₁-C₄alkyl;    -   m is 2-6;    -   n is 0-5;    -   p is 1-3;    -   q is 1-3; or

a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment is a compound of Formula (V) wherein A is O, orN(R₁₀). In another embodiment is a compound of Formula (V) wherein A isO, or N(H). In another embodiment is a compound of Formula (V) wherein Ais O. In another embodiment is a compound of Formula (V) wherein A isN(R₁₀). In another embodiment is a compound of Formula (V) wherein A isN(H). In another embodiment is a compound of Formula (V) wherein A isN(CH₃). In another embodiment is a compound of Formula (V) wherein A isa bond.

In another embodiment is a compound of Formula (V) wherein R₆ issubstituted or unsubstituted C₃-C₈cycloalkyl. In another embodiment is acompound of Formula (V) wherein R₆ is substituted or unsubstitutedcyclopropyl. In another embodiment is a compound of Formula (V) whereinR₆ is substituted or unsubstituted cyclobutyl. In another embodiment isa compound of Formula (V) wherein R₆ is substituted or unsubstitutedcyclopentyl. In another embodiment is a compound of Formula (V) whereinR₆ is substituted or unsubstituted cyclohexyl.

In another embodiment is a compound of Formula (V) wherein R₆ issubstituted or unsubstituted C₂-C₇heteroaryl. In another embodiment is acompound of Formula (V) wherein R₆ is substituted or unsubstitutedfuranyl, thiophenyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl,isoxazolyl, isothiazolyl, pyrazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, indolyl,benzothiophenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, pyrazolopyridinyl,imidazopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, indolizinyl,purinyl, furopyridinyl, thienopyridinyl, furopyrrolyl, furofuranyl,thienofuranyl, 1,4-dihydropyrrolopyrrolyl, thienopyrrolyl,thienothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl,furopyrazolyl, thienopyrazolyl, selenophenyl, selenazolyl, andbenzoisoxazolyl. In another embodiment is a compound of Formula (V)wherein R₆ is substituted or unsubstituted pyridyl. In anotherembodiment is a compound of Formula (V) wherein R₆ is substitutedpyridyl. In another embodiment is a compound of Formula (V) wherein R₆is unsubstituted pyridyl.

In another embodiment is a compound of Formula (V) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁. In another embodiment is a compound of Formula(V) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₂₁, and each R₁₄ and R₁₅ are H. Inanother embodiment is a compound of Formula (V) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁, m is 2, and each R₁₄ and R₁₅ are H. In anotherembodiment is a compound of Formula (V) wherein R₆ is —(CH₂)_(m)R₂₁, mis 2, and R₂₁ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (V) wherein R₆ is—(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted or unsubstitutedC₃-C₈cycloalkyl. In another embodiment is a compound of Formula (V)wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted orunsubstituted C₆-C₁₀aryl. In another embodiment is a compound of Formula(V) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted orunsubstituted phenyl. In another embodiment is a compound of Formula (V)wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted orunsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (V) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is —OH.

In another embodiment is a compound of Formula (V) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁, m is 3, and each R₁₄ and R₁₅ are H. In anotherembodiment is a compound of Formula (V) wherein R₆ is —(CH₂)_(m)R₂₁, mis 3, and R₂₁ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (V) wherein R₆ is—(CH₂)_(m)R₂₁, m is 3, and Rai is substituted or unsubstitutedC₃-C₈cycloalkyl. In another embodiment is a compound of Formula (V)wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted orunsubstituted C₆-C₁₀aryl. In another embodiment is a compound of Formula(V) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted orunsubstituted phenyl. In another embodiment is a compound of Formula (V)wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted orunsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (V) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is —OH.

In another embodiment is a compound of Formula (V) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂). In another embodiment is a compound ofFormula (V) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), m is 2, andeach R₁₄ and R₁₅ are H. In another embodiment is a compound of Formula(V) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ areeach H. In another embodiment is a compound of Formula (V) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is H. In another embodiment is a compound of Formula(V) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is CH₃, and R₁₂ isH. In another embodiment is a compound of Formula (V) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is substituted or unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (V) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, R₁₁ is CH₃, and R₁₂ is CH₃. In anotherembodiment is a compound of Formula (V) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ are taken together toform a 5-, 6-, 7-, or 8-membered heterocyclic ring. In anotherembodiment is a compound of Formula (V) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ and R₁₂ are taken together toform a 5-membered heterocyclic ring. In another embodiment is a compoundof Formula (V) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 2, and R₁₁ andR₁₂ are taken together to form a 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (V) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂). In another embodiment is a compound ofFormula (V) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), m is 3, andeach R₁₄ and R₁₅ are H. In another embodiment is a compound of Formula(V) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ areeach H. In another embodiment is a compound of Formula (V) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is H. In another embodiment is a compound of Formula(V) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is CH₃, and R₁₂ isH. In another embodiment is a compound of Formula (V) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, R₁₁ is substituted or unsubstitutedC₁-C₆alkyl, and R₁₂ is substituted or unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (V) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₂), m is 3, R₁₁ is CH₃, and R₁₂ is CH₃. In anotherembodiment is a compound of Formula (V) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ are taken together toform a 5-, 6-, 7-, or 8-membered heterocyclic ring. In anotherembodiment is a compound of Formula (V) wherein R₆ is—(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ and R₁₂ are taken together toform a 5-membered heterocyclic ring. In another embodiment is a compoundof Formula (V) wherein R₆ is —(CH₂)_(m)N(R₁₁)(R₁₂), m is 3, and R₁₁ andR₁₂ are taken together to form a 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (V) wherein R₆ issubstituted or unsubstituted C₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (V) wherein R₆ is

In another embodiment is a compound of Formula (V) wherein R₆ is

and J is C(H). In another embodiment is a compound of Formula (V)wherein R₆ is

J is C(H), p is 1, and q is 1. In another embodiment is a compound ofFormula (V) wherein R₆ is

J is C(H), p is 2, and q is 1. In another embodiment is a compound ofFormula (V) wherein R₆ is

J is C(H), p is 3, and q is 1. In another embodiment is a compound ofFormula (V) wherein R₆ is

J is C(H), p is 2, and q is 2. In another embodiment is a compound ofFormula (V) wherein R₆ is

J is C(H), p is 1, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (V) whereinR₆ is

J is C(H), p is 2, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (V) whereinR₆ is

J is C(H), p is 3, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (V) whereinR₆ is

J is C(H), p is 2, q is 2, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl.

In another embodiment is a compound of Formula (V) wherein R₆ is

and J is N. In another embodiment is a compound of Formula (V) whereinR₆ is,

J is N, p is 2, and q is 2. In another embodiment is a compound ofFormula (V) wherein R₆ is

J is N, p is 2, q is 2, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl.

In another embodiment is a compound of Formula (V) wherein R₅ ishalogen. In another embodiment is a compound of Formula (V) wherein R₅is —CF₃. In another embodiment is a compound of Formula (V) wherein R₅is unsubstituted C₁-C₆alkyl. In another embodiment is a compound ofFormula (V) wherein R₅ is —CH₃. In another embodiment is a compound ofFormula (V) wherein R₅ is —CH₂CH₃. In another embodiment is a compoundof Formula (V) wherein R₅ is substituted or unsubstitutedC₁-C₆heteroalkyl. In another embodiment is a compound of Formula (V)wherein R₅ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (V) wherein R₅ issubstituted or unsubstituted C₃-C₈cycloalkyl. In another embodiment is acompound of Formula (V) wherein R₅ is substituted or unsubstitutedC₆-C₁₀aryl. In another embodiment is a compound of Formula (V) whereinR₅ is substituted or unsubstituted C₂-C₇heteroaryl.

In another embodiment is a compound of Formula (V) wherein R₂ and R₃ areeach independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl. In another embodiment is a compound of Formula(V) wherein R₂ and R₃ are each H.

In another embodiment is a compound of Formula (V) wherein R₂ and R₃ areeach independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl; and at least one of R₂ and R₃ is not H. Inanother embodiment is a compound of Formula (V) wherein R₂ is H, and R₃is C₁-C₄alkyl. In another embodiment is a compound of Formula (V)wherein R₂ is H, and R₃ is CH₃. In another embodiment is a compound ofFormula (V) wherein R₂ is H, and R₃ is C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (V) wherein R₂ is H, and R₃ iscyclopropyl. In another embodiment is a compound of Formula (V) whereinR₂ is H, and R₃ is cyclopentyl. In another embodiment is a compound ofFormula (V) wherein R₂ is CH₃, and R₃ is CH₃. In another embodiment is acompound of Formula (V) wherein R₂ is C₁-C₄alkyl, and R₃ is H. Inanother embodiment is a compound of Formula (V) wherein R₂ is CH₃, andR₃ is H. In another embodiment is a compound of Formula (V) wherein R₂is C₃-C₆cycloalkyl, and R₃ is H. In another embodiment is a compound ofFormula (V) wherein R₂ is cyclopropyl, and R₃ is H. In anotherembodiment is a compound of Formula (V) wherein R₂ is cyclopentyl, andR₃ is H.

In another embodiment is a compound of Formula (V) wherein R₂ and R₃ aretaken together to form a 5- or 6-membered heterocyclic ring. In anotherembodiment is a compound of Formula (V) wherein R₂ and R₃ are takentogether to form a 5-membered heterocyclic ring. In another embodimentis a compound of Formula (V) wherein R₂ and R₃ are taken together toform 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (V) wherein n is 0.

In another embodiment is a compound of Formula (V) wherein each R₁ isindependently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,—SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉, —C(═O)R₉,—CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (V) wherein each R₁ is independently halogen, —CN, —OH, —CF₃,substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstitutedC₁-C₆alkoxy. In another embodiment is a compound of Formula (V) whereineach R₁ is independently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl, substitutedor unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (V) wherein each R₁ is independently halogen, —CN, —OCF₃,—OCH₂F, —OCF₂H, —CF₃, substituted or unsubstituted C₁-C₆alkyl, orsubstituted or unsubstituted C₁-C₆alkoxy. In another embodiment is acompound of Formula (V) wherein each R₁ is independently halogen, —CN,—OCF₃, —OCH₂F, —OCF₂H, —CF₃, substituted or unsubstituted C₁-C₆alkyl, orsubstituted or unsubstituted C₁-C₆alkoxy, and n is 3. In anotherembodiment is a compound of Formula (V) wherein each R₁ is independentlyhalogen, —CN, —OCF₃, —OCH₂F, —OCF₂H, —CF₃, substituted or unsubstitutedC₁-C₆alkyl, or substituted or unsubstituted C₁-C₆alkoxy, and n is 2. Inanother embodiment is a compound of Formula (V) wherein n is 3, and eachR₁ is independently halogen. In another embodiment is a compound ofFormula (V) wherein n is 2, and each R₁ is independently halogen. Inanother embodiment is a compound of Formula (V) wherein n is 2, and eachR₁ is independently F or Cl. In another embodiment is a compound ofFormula (V) wherein n is 2, and each R₁ is F. In another embodiment is acompound of Formula (V) wherein n is 2, and each R₁ is independently Cl.In another embodiment is a compound of Formula (V) wherein n is 2, andeach R₁ is independently halogen or —CF₃. In another embodiment is acompound of Formula (V) wherein n is 2, and each R₁ is independently For —CF₃. In another embodiment is a compound of Formula (V) wherein n is2, and each R₁ is independently Cl or —CF₃. In another embodiment is acompound of Formula (V) wherein n is 1, and R₁ is halogen. In anotherembodiment is a compound of Formula (V) wherein n is 1, and R₁ is F. Inanother embodiment is a compound of Formula (V) wherein n is 1, and R₁is Cl. In another embodiment is a compound of Formula (V) wherein n is1, and R₁ is —CF₃. In another embodiment is a compound of Formula (V)wherein n is 1, and R₁ is substituted or unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (V) wherein n is 1, and R₁is CH₃. In another embodiment is a compound of Formula (V) wherein n is1, and R₁ is substituted or unsubstituted C₁-C₆alkoxy. In anotherembodiment is a compound of Formula (V) wherein n is 1, and R₁ is —OCH₃.In another embodiment is a compound of Formula (V) wherein n is 1, andR₁ is —OCF₃. In another embodiment is a compound of Formula (V) whereinn is 1, and R₁ is —OCF₂H.

In another aspect, described herein is a compound of Formula (VI):

wherein:

-   -   each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F,        —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,        —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂,        —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆alkoxy, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or        substituted or unsubstituted C₂-C₇heteroaryl;    -   or two R₁ are taken together to form a substituted or        unsubstituted heterocyclic ring or a substituted or        unsubstituted carbocyclic ring;    -   R₂ and R₃ are each independently H or C₁-C₄alkyl; or R₂ and R₃        are taken together to form a 5- or 6-membered heterocyclic ring;    -   R₅ is substituted or unsubstituted C₁-C₆alkyl;    -   R₆ is unsubstituted C₁-C₄alkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, substituted or unsubstituted        C₃-C₈cycloalkyl, substituted or unsubstituted C₂-C₇heteroaryl,        —(C(R₁₄)(R₁₅))_(m)R₂₁,

-   -   J is C(H);    -   R₁₃ is H, substituted or unsubstituted C₁-C₆alkyl, substituted        or unsubstituted C₂-C₇heterocycloalkyl, substituted or        unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted        —C₁-C₄alkylC₆-C₁₀aryl, or substituted or unsubstituted        —C₁-C₄alkyC₂-C₇heteroaryl;    -   each R₁₄ and R₁₅ are each independently H, halogen, or        substituted or unsubstituted C₁-C₆alkyl;    -   R₂₁ is halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,        —SR₂₂, —N(R₂₂)S(═O)₂R₂₃, —S(═O)₂N(R₂₂)₂, —S(═O)R₂₃, —S(═O)₂R₂₃,        —C(═O)R₂₃, —CO₂R₂₂, —C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substituted        or unsubstituted C₁-C₆alkoxy, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted        C₂-C₇heterocycloalkyl, or substituted or unsubstituted        C₂-C₇heteroaryl;    -   each R₂₂ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₂₃ is substituted or unsubstituted C₁-C₆alkyl;    -   each R₈ is independently H, or substituted or unsubstituted        C₁-C₆alkyl;    -   R₉ is substituted or unsubstituted C₁-C₆alkyl;    -   R₁₀ is H;    -   m is 2-6;    -   n is 0-5;    -   p is 1-3;    -   q is 1-3; or

a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment is a compound of Formula (VI) wherein R₆ issubstituted or unsubstituted C₃-C₈cycloalkyl. In another embodiment is acompound of Formula (VI) wherein R₆ is substituted or unsubstitutedcyclopropyl. In another embodiment is a compound of Formula (VI) whereinR₆ is substituted or unsubstituted cyclobutyl. In another embodiment isa compound of Formula (VI) wherein R₆ is substituted or unsubstitutedcyclopentyl. In another embodiment is a compound of Formula (VI) whereinR₆ is substituted or unsubstituted cyclohexyl.

In another embodiment is a compound of Formula (VI) wherein R₆ issubstituted or unsubstituted C₂-C₇heteroaryl. In another embodiment is acompound of Formula (VI) wherein R₆ is substituted or unsubstitutedfuranyl, thiophenyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl,isoxazolyl, isothiazolyl, pyrazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, indolyl,benzothiophenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, pyrazolopyridinyl,imidazopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, indolizinyl,purinyl, furopyridinyl, thienopyridinyl, furopyrrolyl, furofuranyl,thienofuranyl, 1,4-dihydropyrrolopyrrolyl, thienopyrrolyl,thienothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl,furopyrazolyl, thienopyrazolyl, selenophenyl, selenazolyl, andbenzoisoxazolyl. In another embodiment is a compound of Formula (VI)wherein R₆ is substituted or unsubstituted pyridyl. In anotherembodiment is a compound of Formula (VI) wherein R₆ is substitutedpyridyl. In another embodiment is a compound of Formula (VI) wherein R₆is unsubstituted pyridyl.

In another embodiment is a compound of Formula (VI) wherein R₆ isunsubstituted C₁-C₄alkyl. In another embodiment is a compound of Formula(VI) wherein R₆ is —CH₃. In another embodiment is a compound of Formula(VI) wherein R₆ is —CH₂CH₃. In another embodiment is a compound ofFormula (VI) wherein R₆ is —CH₂CH₂CH₃.

In another embodiment is a compound of Formula (VI) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁. In another embodiment is a compound of Formula(VI) wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₂₁, and each R₁₄ and R₁₅ are H orhalogen. In another embodiment is a compound of Formula (VI) wherein R₆is —(C(R₁₄)(R₁₅))_(m)R₂₁, and each R₁₄ and R₁₅ are H or halogen. Inanother embodiment is a compound of Formula (VI) wherein R₆ is—(C(R₁₄)(R₁))_(m)R₂₁, m is 2, and each R₁₄ and R₁₅ are H. In anotherembodiment is a compound of Formula (VI) wherein R₆ is —(CH₂)_(m)R₂₁, mis 2, and R₂₁ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (VI) wherein R₆ is—(CH₂)_(m)R₂₁, m is 2, and R₂₁ is substituted or unsubstitutedC₂-C₇heteroaryl. In another embodiment is a compound of Formula (VI)wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is —OH. In anotherembodiment is a compound of Formula (VI) wherein R₆ is —(CH₂)_(m)R₂₁, mis 2, and R₂₁ is —N(R₂₂)S(═O)₂R₂₃. In another embodiment is a compoundof Formula (VI) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is—N(H)S(═O)₂CH₃. In another embodiment is a compound of Formula (VI)wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is —N(R₂₂)C(═O)R₂₃. Inanother embodiment is a compound of Formula (VI) wherein R₆ is—(CH₂)_(m)R₂₁, m is 2, and R₂₁ is —N(H)C(═O)CH₃. In another embodimentis a compound of Formula (VI) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, andR₂₁ is —C(═O)N(R₂₂)₂. In another embodiment is a compound of Formula(VI) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is —C(═O)NH₂. Inanother embodiment is a compound of Formula (VI) wherein R₆ is—(CH₂)_(m)R₂₁, m is 2, and R₂₁ is —CO₂R₂₂. In another embodiment is acompound of Formula (VI) wherein R₆ is —(CH₂)_(m)R₂₁, m is 2, and R₂₁ is—CO₂Et.

In another embodiment is a compound of Formula (VI) wherein R₆ is—(C(R₁₄)(R₁₅))_(m)R₂₁, m is 3, and each R₁₄ and R₁₅ are H. In anotherembodiment is a compound of Formula (VI) wherein R₆ is —(CH₂)_(m)R₂₁, mis 3, and R₂₁ is substituted or unsubstituted C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (VI) wherein R₆ is—(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted or unsubstitutedC₃-C₈cycloalkyl. In another embodiment is a compound of Formula (VI)wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted C₆-C₁₀aryl.In another embodiment is a compound of Formula (VI) wherein R₆ is—(CH₂)_(m)R₂₁, m is 3, and R₂₁ is substituted phenyl. In anotherembodiment is a compound of Formula (VI) wherein R₆ is —(CH₂)_(m)R₂₁, mis 3, and R₂₁ is substituted or unsubstituted C₂-C₇heteroaryl. Inanother embodiment is a compound of Formula (VI) wherein R₆ is—(CH₂)_(m)R₂₁, m is 3, and R₂₁ is —OH. In another embodiment is acompound of Formula (VI) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is—N(R₂₂)S(═O)₂R₂₃. In another embodiment is a compound of Formula (VI)wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is —N(H)S(═O)₂CH₃. Inanother embodiment is a compound of Formula (VI) wherein R₆ is—(CH₂)_(m)R₂₁, m is 3, and R₂₁ is —N(R₂₂)C(═O)R₂₃. In another embodimentis a compound of Formula (VI) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, andR₂₁ is —N(H)C(═O)CH₃. In another embodiment is a compound of Formula(VI) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is —C(═O)N(R₂₂)₂. Inanother embodiment is a compound of Formula (VI) wherein R₆ is—(CH₂)_(m)R₂₁, m is 3, and R₂₁ is —C(═O)NH₂. In another embodiment is acompound of Formula (VI) wherein R₆ is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is—CO₂R₂₂. In another embodiment is a compound of Formula (VI) wherein R₆is —(CH₂)_(m)R₂₁, m is 3, and R₂₁ is —CO₂Et.

In another embodiment is a compound of Formula (VI) wherein R₆ issubstituted or unsubstituted C₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (VI) wherein R₆ is

and J is C(H). In another embodiment is a compound of Formula (VI)wherein R₆ is

J is C(H), p is 1, and q is 1. In another embodiment is a compound ofFormula (VI) wherein R₆ is

J is C(H), p is 2, and q is 1. In another embodiment is a compound ofFormula (VI) wherein R₆ is

J is C(H), p is 3, and q is 1. In another embodiment is a compound ofFormula (VI) wherein R₆ is

J is C(H), p is 2, and q is 2. In another embodiment is a compound ofFormula (VI) wherein R₆ is

J is C(H), p is 1, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (VI) whereinR₆ is

J is C(H), p is 2, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (VI) whereinR₆ is

J is C(H), p is 3, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (VI) whereinR₆ is

J is C(H), p is 2, q is 2, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl.

In another embodiment is a compound of Formula (VI) wherein R₆ issubstituted or unsubstituted C₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (VI) wherein R₆ is

and J is C(H). In another embodiment is a compound of Formula (VI)wherein R₆ is

J is C(H), p is 1, and q is 1. In another embodiment is a compound ofFormula (VI) wherein R₆ is

J is C(H), p is 2, and q is 1. In another embodiment is a compound ofFormula (VI) wherein R₆ is

J is C(H), p is 3, and q is 1. In another embodiment is a compound ofFormula (VI) wherein R₆ is

J is C(H), p is 2, and q is 2. In another embodiment is a compound ofFormula (VI) wherein R₆ is

J is C(H), p is 1, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (VI) whereinR₆ is

J is C(H), p is 2, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (VI) whereinR₆ is

J is C(H), p is 3, q is 1, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (VI) whereinR₆ is

J is C(H), p is 2, q is 2, and R₁₃ is substituted or unsubstitutedC₁-C₆alkyl.

In another embodiment is a compound of Formula (VI) wherein R₅ issubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(VI) wherein R₅ is unsubstituted C₁-C₆alkyl. In another embodiment is acompound of Formula (VI) wherein R₅ is unsubstituted —CH₃. In anotherembodiment is a compound of Formula (VI) wherein R₅ is unsubstituted—CH₂CH₃.

In another embodiment is a compound of Formula (VI) wherein R₂ and R₃are each H. In another embodiment is a compound of Formula (VI) whereinR₂ and R₃ are each independently H or C₁-C₄alkyl; and at least one of R₂and R₃ is not H. In another embodiment is a compound of Formula (VI)wherein R₂ is H, and R₃ is C₁-C₄alkyl. In another embodiment is acompound of Formula (VI) wherein R₂ is H, and R₃ is CH₃. In anotherembodiment is a compound of Formula (VI) wherein R₂ is CH₃, and R₃ isCH₃. In another embodiment is a compound of Formula (VI) wherein R₂ isC₁-C₄alkyl, and R₃ is H. In another embodiment is a compound of Formula(VI) wherein R₂ is CH₃, and R₃ is H.

In another embodiment is a compound of Formula (VI) wherein R₂ and R₃are taken together to form a 5- or 6-membered heterocyclic ring. Inanother embodiment is a compound of Formula (VI) wherein R₂ and R₃ aretaken together to form a 5-membered heterocyclic ring. In anotherembodiment is a compound of Formula (VI) wherein R₂ and R₃ are takentogether to form 6-membered heterocyclic ring.

In another embodiment is a compound of Formula (VI) wherein n is 0.

In another embodiment is a compound of Formula (VI) wherein each R₁ isindependently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —SR₈,—N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈,—N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉, substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy, substituted orunsubstituted C₁-C₆heteroalkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₃-C₈cycloalkyl,substituted or unsubstituted C₆-C₁₀aryl, or substituted or unsubstitutedC₂-C₇heteroaryl. In another embodiment is a compound of Formula (VI)wherein each R₁ is independently halogen, —CN, —OH, substituted orunsubstituted C₁-C₆alkyl, or substituted or unsubstituted C₁-C₆alkoxy.In another embodiment is a compound of Formula (VI) wherein each R₁ isindependently halogen, —CN, —OCF₃, —OCH₂F, —OCF₂H, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl. In another embodiment is a compound ofFormula (VI) wherein each R₁ is independently halogen, —CN, —OCF₃,—OCH₂F, —OCF₂H, substituted or unsubstituted C₁-C₆alkyl, or substitutedor unsubstituted C₁-C₆alkoxy. In another embodiment is a compound ofFormula (VI) wherein each R₁ is independently halogen, —CN, —OCF₃,—OCH₂F, —OCF₂H, substituted or unsubstituted C₁-C₆alkyl, or substitutedor unsubstituted C₁-C₆alkoxy, and n is 3. In another embodiment is acompound of Formula (VI) wherein each R₁ is independently halogen, —CN,—OCF₃, —OCH₂F, —OCF₂H, substituted or unsubstituted C₁-C₆alkyl, orsubstituted or unsubstituted C₁-C₆alkoxy, and n is 2. In anotherembodiment is a compound of Formula (VI) wherein n is 3, and each R₁ isindependently halogen. In another embodiment is a compound of Formula(VI) wherein n is 2, and each R₁ is independently halogen. In anotherembodiment is a compound of Formula (VI) wherein n is 2, and each R₁ isindependently F or Cl. In another embodiment is a compound of Formula(VI) wherein n is 2, and one R₁ is F and one R₁ is —CF₃. In anotherembodiment is a compound of Formula (VI) wherein n is 2, and each R₁ isF. In another embodiment is a compound of Formula (VI) wherein n is 2,and each R₁ is Cl. In another embodiment is a compound of Formula (VI)wherein n is 2, and one R₁ is F and one R₁ is Cl. In another embodimentis a compound of Formula (VI) wherein n is 1, and R₁ is halogen. Inanother embodiment is a compound of Formula (VI) wherein n is 1, and R₁is F. In another embodiment is a compound of Formula (VI) wherein n is1, and R₁ is Cl. In another embodiment is a compound of Formula (VI)wherein n is 1, and R₁ is substituted or unsubstituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (VI) wherein n is 1, and R₁is CH₃. In another embodiment is a compound of Formula (VI) wherein n is1, and R₁ is —CF₃. In another embodiment is a compound of Formula (VI)wherein n is 1, and R₁ is substituted or unsubstituted C₁-C₆alkoxy. Inanother embodiment is a compound of Formula (VI) wherein n is 1, and R₁is —OCH₃. In another embodiment is a compound of Formula (VI) wherein nis 1, and R₁ is —OCF₃. In another embodiment is a compound of Formula(VI) wherein n is 1, and R₁ is —OCF₂H.

In another embodiment is a compound selected from:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Deuterium (D or ²H) is a stable, non-radioactive isotope of hydrogen andhas an atomic weight of 2.0144. Hydrogen naturally occurs as a mixtureof the isotopes ¹H (hydrogen or protium), D (²H or deuterium), and T (³Hor tritium). The natural abundance of deuterium is 0.015%. Generally, inchemical compounds with an H atom, the H atom actually represents amixture of H and D, with about 0.015% being D. In some embodiments,deuterium-enriched compounds described herein are achieved by eitherexchanging protons with deuterium or via starting materials and/orintermediates enriched with deuterium.

Any combination of the groups described above for the various variablesis contemplated herein.

Throughout the specification, groups and substituents thereof can bechosen to provide stable moieties and compounds.

Further Forms of Compounds

The compounds described herein may in some cases exist as diastereomers,enantiomers, or other stereoisomeric forms. The compounds presentedherein include all diastereomeric, enantiomeric, and epimeric forms aswell as the appropriate mixtures thereof. Separation of stereoisomersmay be performed by chromatography or by the forming diastereomeric andseparation by recrystallization, or chromatography, or any combinationthereof (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers,Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, hereinincorporated by reference for this disclosure). Stereoisomers may alsobe obtained by stereoselective synthesis.

In some situations, compounds may exist as tautomers. All tautomers areincluded within the formulas described herein.

The methods and compositions described herein include the use ofamorphous forms as well as crystalline forms (also known as polymorphs).The compounds described herein may be in the form of pharmaceuticallyacceptable salts. As well, active metabolites of these compounds havingthe same type of activity are included in the scope of the presentdisclosure. In addition, the compounds described herein can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

In some embodiments, compounds described herein may be prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. An example, withoutlimitation, of a prodrug would be a compound described herein, which isadministered as an ester (the “prodrug”) to facilitate transmittalacross a cell membrane where water solubility is detrimental to mobilitybut which then is metabolically hydrolyzed to the carboxylic acid, theactive entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically active form of the compound. Incertain embodiments, a prodrug is enzymatically metabolized by one ormore steps or processes to the biologically, pharmaceutically ortherapeutically active form of the compound.

To produce a prodrug, a pharmaceutically active compound is modifiedsuch that the active compound will be regenerated upon in vivoadministration. The prodrug can be designed to alter the metabolicstability or the transport characteristics of a drug, to mask sideeffects or toxicity, to improve the flavor of a drug or to alter othercharacteristics or properties of a drug. In some embodiments, by virtueof knowledge of pharmacodynamic processes and drug metabolism in vivo,once a pharmaceutically active compound is determined, prodrugs of thecompound are designed. (see, for example, Nogrady (1985) MedicinalChemistry A Biochemical Approach, Oxford University Press, New York,pages 388-392; Silverman (1992), The Organic Chemistry of Drug Designand Drug Action, Academic Press, Inc., San Diego, pages 352-401,Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters,Vol. 4, p. 1985; Rooseboom et al., Pharmacological Reviews, 56:53-102,2004; Miller et al., J. Med. Chem. Vol. 46, no. 24, 5097-5116, 2003;Aesop Cho, “Recent Advances in Oral Prodrug Discovery”, Annual Reportsin Medicinal Chemistry, Vol. 41, 395-407, 2006).

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a compound of Formula (I), (II), (IIA),(IIB), (IIC), (IID), (III), (IV), (V) or (VI) as set forth herein areincluded within the scope of the claims. In some cases, some of theherein-described compounds may be a prodrug for another derivative oractive compound.

Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. Prodrugs may be designed as reversible drugderivatives, for use as modifiers to enhance drug transport tosite-specific tissues. In some embodiments, the design of a prodrugincreases the effective water solubility. See, e.g., Fedorak et al., Am.J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol,106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992);J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J.Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J.Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs asNovel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; andEdward B. Roche, Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, all incorporatedherein for such disclosure).

Sites on the aromatic ring portion of compounds described herein can besusceptible to various metabolic reactions, therefore incorporation ofappropriate substituents on the aromatic ring structures, such as, byway of example only, halogens can reduce, minimize or eliminate thismetabolic pathway.

The compounds described herein may be labeled isotopically (e.g. with aradioisotope) or by other means, including, but not limited to, the useof chromophores or fluorescent moieties, bioluminescent labels,photoactivatable or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, suchas, for example, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl,respectively. Certain isotopically-labeled compounds described herein,for example those into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Further, substitution with isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, such as, for example, increased in vivo half-lifeor reduced dosage requirements.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

Compounds described herein may be formed as, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formedby reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid, such as, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid,and the like; or with an organic acid, such as, for example, aceticacid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaricacid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, toluenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, butyric acid, phenylacetic acid,phenylbutyric acid, valproic acid, and the like; (2) salts formed whenan acidic proton present in the parent compound is replaced by a metalion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), analkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. Insome cases, compounds described herein may coordinate with an organicbase, such as, but not limited to, ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine,tris(hydroxymethyl)methylamine. In other cases, compounds describedherein may form salts with amino acids such as, but not limited to,arginine, lysine, and the like. Acceptable inorganic bases used to formsalts with compounds that include an acidic proton, include, but are notlimited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide,sodium carbonate, sodium hydroxide, and the like.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. Solvates of compounds described herein can beconveniently prepared or formed during the processes described herein.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

In some embodiments, compounds described herein, such as compounds ofFormula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI),are in various forms, including but not limited to, amorphous forms,milled forms and nano-particulate forms. In addition, compoundsdescribed herein include crystalline forms, also known as polymorphs.Polymorphs include the different crystal packing arrangements of thesame elemental composition of a compound. Polymorphs usually havedifferent X-ray diffraction patterns, melting points, density, hardness,crystal shape, optical properties, stability, and solubility. Variousfactors such as the recrystallization solvent, rate of crystallization,and storage temperature may cause a single crystal form to dominate.

The screening and characterization of the pharmaceutically acceptablesalts, polymorphs and/or solvates may be accomplished using a variety oftechniques including, but not limited to, thermal analysis, x-raydiffraction, spectroscopy, vapor sorption, and microscopy. Thermalanalysis methods address thermo chemical degradation or thermo physicalprocesses including, but not limited to, polymorphic transitions, andsuch methods are used to analyze the relationships between polymorphicforms, determine weight loss, to find the glass transition temperature,or for excipient compatibility studies. Such methods include, but arenot limited to, Differential Scanning Calorimetry (DSC), ModulatedDifferential Scanning Calorimetry (MDCS), Thermogravimetric analysis(TGA), and Thermogravi-metric and Infrared analysis (TG/IR). X-raydiffraction methods include, but are not limited to, single crystal andpowder diffractometers and synchrotron sources. The variousspectroscopic techniques used include, but are not limited to, Raman,FTIR, UV-VIS, and NMR (liquid and solid state). The various microscopytechniques include, but are not limited to, polarized light microscopy,Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis(EDX), Environmental Scanning Electron Microscopy with EDX (in gas orwater vapor atmosphere), IR microscopy, and Raman microscopy.

Throughout the specification, groups and substituents thereof can bechosen to provide stable moieties and compounds.

Synthesis of Compounds

In some embodiments, the synthesis of compounds described herein areaccomplished using means described in the chemical literature, using themethods described herein, or by a combination thereof. In addition,solvents, temperatures and other reaction conditions presented hereinmay vary.

In some embodiments, compounds of Formula (I), (II), (IIA), (IIB),(IIC), (IID), (III), (IV), (V) or (VI) are prepared according to thesynthetic route shown in Scheme 1.

As depicted in Scheme 1, addition of the amine to the isocyanate givesthe urea.

Through a similar protocol, additional compounds of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI) are prepared asshown in Scheme 2.

In some embodiments, the isocyanate and amine synthetic intermediatesare prepared according to Schemes 3-4.

In other embodiments, the starting materials and reagents used for thesynthesis of the compounds described herein are synthesized or areobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.

In further embodiments, the compounds described herein, and otherrelated compounds having different substituents are synthesized usingtechniques and materials described herein as well as those that arerecognized in the field, such as described, for example, in Fieser andFieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley andSons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, ADVANCED ORGANICCHEMISTRY 4^(th) Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANICCHEMISTRY 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), and Greene andWuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^(rd) Ed., (Wiley 1999)(all of which are incorporated by reference for such disclosure).

Certain Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood to which the claimedsubject matter belongs. In the event that there are a plurality ofdefinitions for terms herein, those in this section prevail. Allpatents, patent applications, publications and published nucleotide andamino acid sequences (e.g., sequences available in GenBank or otherdatabases) referred to herein are incorporated by reference. Wherereference is made to a URL or other such identifier or address, it isunderstood that such identifiers can change and particular informationon the internet can come and go, but equivalent information can be foundby searching the internet. Reference thereto evidences the availabilityand public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

Definition of standard chemistry terms may be found in reference works,including but not limited to, Carey and Sundberg “ADVANCED ORGANICCHEMISTRY 4^(TH) ED.” Vols. A (2000) and B (2001), Plenum Press, NewYork. Unless otherwise indicated, conventional methods of massspectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinantDNA techniques and pharmacology.

Unless specific definitions are provided, the nomenclature employed inconnection with, and the laboratory procedures and techniques of,analytical chemistry, synthetic organic chemistry, and medicinal andpharmaceutical chemistry described herein are those recognized in thefield. Standard techniques can be used for chemical syntheses, chemicalanalyses, pharmaceutical preparation, formulation, and delivery, andtreatment of patients. Standard techniques can be used for recombinantDNA, oligonucleotide synthesis, and tissue culture and transformation(e.g., electroporation, lipofection). Reactions and purificationtechniques can be performed e.g., using kits of manufacturer'sspecifications or as commonly accomplished in the art or as describedherein. The foregoing techniques and procedures can be generallyperformed of conventional methods and as described in various generaland more specific references that are cited and discussed throughout thepresent specification.

It is to be understood that the methods and compositions describedherein are not limited to the particular methodology, protocols, celllines, constructs, and reagents described herein and as such may vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the methods, compounds, compositions describedherein.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). C₁-C_(x)refers to the number of carbon atoms that make up the moiety to which itdesignates (excluding optional substituents).

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylgroups may or may not include units of unsaturation. The alkyl moietymay be a “saturated alkyl” group, which means that it does not containany units of unsaturation (i.e. a carbon-carbon double bond or acarbon-carbon triple bond). The alkyl group may also be an “unsaturatedalkyl” moiety, which means that it contains at least one unit ofunsaturation. The alkyl moiety, whether saturated or unsaturated, may bebranched, straight chain, or cyclic.

The “alkyl” group may have 1 to 12 carbon atoms (whenever it appearsherein, a numerical range such as “1 to 6” refers to each integer in thegiven range; e.g., “1 to 6 carbon atoms” means that the alkyl group mayconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up toand including 6 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated). The alkyl group of the compounds described herein may bedesignated as “C₁-C₆ alkyl” or similar designations. By way of exampleonly, “C₁-C₆ alkyl” indicates that there are one to six carbon atoms inthe alkyl chain, i.e., the alkyl chain is selected from the groupconsisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, hexyl, propen-3-yl(allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl. Alkyl groups can be substituted or unsubstituted.Depending on the structure, an alkyl group can be a monoradical or adiradical (i.e., an alkylene group).

An “alkoxy” refers to a “—O-alkyl” group, where alkyl is as definedherein.

The term “alkenyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a double bond that is not part of anaromatic group. That is, an alkenyl group begins with the atoms—C(R)═CR₂, wherein R refers to the remaining portions of the alkenylgroup, which may be the same or different. Non-limiting examples of analkenyl group include —CH═CH₂, —C(CH₃)═CH₂, —CH═CHCH₃, —CH═C(CH₃)₂ and—C(CH₃)═CHCH₃. The alkenyl moiety may be branched, straight chain, orcyclic (in which case, it would also be known as a “cycloalkenyl”group). Alkenyl groups may have 2 to 6 carbons. Alkenyl groups can besubstituted or unsubstituted. Depending on the structure, an alkenylgroup can be a monoradical or a diradical (i.e., an alkenylene group).

The term “alkynyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a triple bond. That is, an alkynylgroup begins with the atoms —C≡C—R, wherein R refers to the remainingportions of the alkynyl group. Non-limiting examples of an alkynyl groupinclude —C≡CH, —C≡CCH₃, —C≡CCH₂CH₃ and —C≡CCH₂CH₂CH₃. The “R” portion ofthe alkynyl moiety may be branched, straight chain, or cyclic. Analkynyl group can have 2 to 6 carbons. Alkynyl groups can be substitutedor unsubstituted. Depending on the structure, an alkynyl group can be amonoradical or a diradical (i.e., an alkynylene group).

“Amino” refers to a —NH₂ group.

The term “alkylamine” or “alkylamino” refers to the —N(alkyl)_(x)H_(y)group, where alkyl is as defined herein and x and y are selected fromthe group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, takentogether with the nitrogen to which they are attached, can optionallyform a cyclic ring system. “Dialkylamino” refers to a —N(alkyl)₂ group,where alkyl is as defined herein.

The term “aromatic” refers to a planar ring having a delocalizedπ-electron system containing 4n+2π electrons, where n is an integer.Aromatic rings can be formed from five, six, seven, eight, nine, or morethan nine atoms. Aromatics can be optionally substituted. The term“aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) andheteroaryl groups (e.g., pyridinyl, quinolinyl).

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl rings can be formedby five, six, seven, eight, nine, or more than nine carbon atoms. Arylgroups can be optionally substituted. Examples of aryl groups include,but are not limited to phenyl, and naphthalenyl. Depending on thestructure, an aryl group can be a monoradical or a diradical (i.e., anarylene group).

The term “carbocyclic ring” refers to a ring wherein each of the atomsforming the ring is a carbon atom. The carbocyclic ring may be aryl orcycloalkyl.

“Carboxy” refers to —CO₂H. In some embodiments, carboxy moieties may bereplaced with a “carboxylic acid bioisostere”, which refers to afunctional group or moiety that exhibits similar physical and/orchemical properties as a carboxylic acid moiety. A carboxylic acidbioisostere has similar biological properties to that of a carboxylicacid group. A compound with a carboxylic acid moiety can have thecarboxylic acid moiety exchanged with a carboxylic acid bioisostere andhave similar physical and/or biological properties when compared to thecarboxylic acid-containing compound. For example, in one embodiment, acarboxylic acid bioisostere would ionize at physiological pH to roughlythe same extent as a carboxylic acid group. Examples of bioisosteres ofa carboxylic acid include, but are not limited to,

and the like.

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical, wherein each of the atoms forming the ring (i.e. skeletalatoms) is a carbon atom. Cycloalkyls may be saturated, or partiallyunsaturated. Cycloalkyls may be fused with an aromatic ring (in whichcase the cycloalkyl is bonded through a non-aromatic ring carbon atom).Cycloalkyl groups include groups having from 3 to 10 ring atoms.Illustrative examples of cycloalkyl groups include, but are not limitedto, the following moieties:

and the like.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom. Polycyclic heteroarylgroups may be fused or non-fused. Illustrative examples of heteroarylgroups include the following moieties:

and the like.

A “heterocycloalkyl” group or “heteroalicyclic” group refers to acycloalkyl group, wherein at least one skeletal ring atom is aheteroatom selected from nitrogen, oxygen and sulfur. The radicals maybe fused with an aryl or heteroaryl. Illustrative examples ofheterocycloalkyl groups, also referred to as non-aromatic heterocycles,include:

and the like. The term heteroalicyclic also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Unless otherwise noted,heterocycloalkyls have from 2 to 10 carbons in the ring. It isunderstood that when referring to the number of carbon atoms in aheterocycloalkyl, the number of carbon atoms in the heterocycloalkyl isnot the same as the total number of atoms (including the heteroatoms)that make up the heterocycloalkyl (i.e. skeletal atoms of theheterocycloalkyl ring).

The term “heterocyclic ring” refers to a ring wherein at least oneskeletal ring atom is a heteroatom selected from nitrogen, oxygen andsulfur. The heterocyclic ring may be heteroaryl or heterocycloalkyl.

The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromoand iodo.

The term “haloalkyl” refers to an alkyl group that is substituted withone or more halogens. The halogens may the same or they may bedifferent. Non-limiting examples of haloalkyls include —CH₂Cl, —CF₃,—CHF₂, —CH₂CF₃, —CF₂CF₃, —CF(CH₃)₃, and the like.

The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxygroups, respectively, that are substituted with one or more fluorineatoms. Non-limiting examples of fluoroalkyls include —CF₃, —CHF₂, —CH₂F,—CH₂CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CF(CH₃)₃, and the like. Non-limitingexamples of fluoroalkoxy groups, include —OCF₃, —OCHF₂, —OCH₂F,—OCH₂CF₃, —OCF₂CF₃, —OCF₂CF₂CF₃, —OCF(CH₃)₂, and the like.

The term “heteroalkyl” refers to an alkyl radical where one or moreskeletal chain atoms is selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof.The heteroatom(s) may be placed at any interior position of theheteroalkyl group. Examples include, but are not limited to, —CH₂—O—CH₃,—CH₂—CH₂—O—CH₃, —CH₂—NH—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—N(CH₃)—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH₂—NH—OCH₃, —CH₂—O—Si(CH₃)₃,—CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. In addition, up to twoheteroatoms may be consecutive, such as, by way of example, —CH₂—NH—OCH₃and —CH₂—O—Si(CH₃)₃. Excluding the number of heteroatoms, a“heteroalkyl” may have from 1 to 6 carbon atoms.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

As used herein, the substituent “R” appearing by itself and without anumber designation refers to a substituent selected from among fromalkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl(bonded through a ring carbon), and heterocycloalkyl.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heterocycloalkyl, —OH, alkoxy, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, —CN, alkyne,C₁-C₆alkylalkyne, halo, acyl, acyloxy, —CO₂H, —CO₂-alkyl, nitro,haloalkyl, fluoroalkyl, and amino, including mono- and di-substitutedamino groups (e.g. —NH₂, —NHR, —N(R₈)₂), and the protected derivativesthereof. By way of example, an optional substituents may be L^(s)R^(s),wherein each L^(s) is independently selected from a bond, —O—, —C(═O)—,—S—, —S(═O)—, —S(═O)₂—, —NH—, —NHC(O)—, —C(O)NH—, —S(═O)₂NH—,—NHS(═O)₂—, —OC(O)NH—, —NHC(O)O—, —(C₁-C₆alkyl)-, or —(C₂-C₆alkenyl)-;and each R^(s) is independently selected from among H, (C₁-C₆alkyl),(C₃-C₈cycloalkyl), aryl, heteroaryl, heterocycloalkyl, andC₁-C₆heteroalkyl. The protecting groups that may form the protectivederivatives of the above substituents are found in sources such asGreene and Wuts, above.

The methods and formulations described herein include the use ofcrystalline forms (also known as polymorphs), or pharmaceuticallyacceptable salts of compounds having the structure of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI), as well as activemetabolites of these compounds having the same type of activity. In somesituations, compounds may exist as tautomers. All tautomers are includedwithin the scope of the compounds presented herein. In addition, thecompounds described herein can exist in unsolvated as well as solvatedforms with pharmaceutically acceptable solvents such as water, ethanol,and the like. The solvated forms of the compounds presented herein arealso considered to be disclosed herein.

The terms “kit” and “article of manufacture” are used as synonyms.

The term “subject” or “patient” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the methods andcompositions provided herein, the mammal is a human.

The terms “disease” or “condition” refer to a state of being or healthstatus of a patient or subject capable of being treated with thecompounds or methods provided herein. In embodiments, the disease is adisease related to (e.g. caused by) Olig2 or aberrant Olig2 activity(e.g. brain cancer, glioblastoma multiforme, medulloblastoma,astrocytomas, brain stem gliomas, meningiomas, oligodendrogliomas,melanomas, lung cancers, breast cancer, leukemias, or Down's Syndrome).Examples of diseases, disorders, or conditions include, but are notlimited to brain cancer, glioblastoma multiforme, medulloblastoma,astrocytomas, brain stem gliomas, meningiomas, oligodendrogliomas,melanomas, lung cancers, breast cancer, leukemias, Down's Syndrome,colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma,Alzheimer's disease, Parkinson's disease, Huntington's Disease,frontotemporal dementia, Creutzfeldt-Jakob disease,Gerstmann-Sträussler-Scheinker syndrome, prion disease,neurodegenerative diseases, cancer, cardiovascular disease,hypertension, Syndrome X, depression, anxiety, glaucoma, humanimmunodeficiency virus (HIV) or acquired immunodeficiency syndrome(AIDS), neurodegeneration, Alzheimer's disease, Parkinson's disease,cognition enhancement, Cushing's Syndrome, Addison's Disease,osteoporosis, frailty, muscle frailty, inflammatory diseases,osteoarthritis, rheumatoid arthritis, asthma and rhinitis, adrenalfunction-related ailments, viral infection, immunodeficiency,immunomodulation, autoimmune diseases, allergies, wound healing,compulsive behavior, multi-drug resistance, addiction, psychosis,anorexia, cachexia, post-traumatic stress syndrome, post-surgical bonefracture, medical catabolism, major psychotic depression, mild cognitiveimpairment, psychosis, dementia, hyperglycemia, stress disorders,antipsychotic induced weight gain, delirium, cognitive impairment indepressed patients, cognitive deterioration in individuals with Down'ssyndrome, psychosis associated with interferon-alpha therapy, chronicpain, pain associated with gastroesophageal reflux disease, postpartumpsychosis, postpartum depression, neurological disorders in prematureinfants, migraine headaches, stroke, aneurysm, brain aneurysm, cerebralaneurysm, brain attack, cerebrovascular accident, ischemia, thrombosis,arterial embolism, hemorrhage, transient ischemic attack, anemia,embolism, systemic hypoperfusion, venous thrombosis, arthritis,reperfusion injury, skin diseases or conditions, acne, acne vulgaris,keratosis pilaris, acute, promyelocytic leukemia, baldness, acnerosacea, harlequin ichthyosis, xeroderma pigmentosum, keratoses,neuroblastoma, fibrodysplasia ossificans progressive, eczema, rosacea,sun damage, wrinkles, or cosmetic conditions. In some instances,“disease” or “condition” refer to cancer. In some further instances,“cancer” refers to human cancers and carcinomas, sarcomas,adenocarcinomas, lymphomas, leukemias, etc., including solid andlymphoid cancers, kidney, breast, lung, bladder, colon, ovarian,prostate, pancreas, stomach, brain, head and neck, skin, uterine,testicular, glioma, esophagus, and liver cancer, includinghepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma,non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Celllymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML),or multiple myeloma.

As used herein, the term “cancer” refers to all types of cancer,neoplasm or malignant tumors found in mammals, including leukemia,carcinomas and sarcomas. Exemplary cancers that may be treated with acompound or method provided herein include cancer of the thyroid,endocrine system, brain, breast, cervix, colon, head & neck, liver,kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary,sarcoma, stomach, uterus or Medulloblastoma. Additional examplesinclude, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma,neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer,rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia,primary brain tumors, cancer, malignant pancreatic insulanoma, malignantcarcinoid, urinary bladder cancer, premalignant skin lesions, testicularcancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer,genitourinary tract cancer, malignant hypercalcemia, endometrial cancer,adrenal cortical cancer, neoplasms of the endocrine or exocrinepancreas, medullary thyroid cancer, medullary thyroid carcinoma,melanoma, colorectal cancer, papillary thyroid cancer, hepatocellularcarcinoma, or prostate cancer.

The term “leukemia” refers broadly to progressive, malignant diseases ofthe blood-forming organs and is generally characterized by a distortedproliferation and development of leukocytes and their precursors in theblood and bone marrow. Leukemia is generally clinically classified onthe basis of (1) the duration and character of the disease-acute orchronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid(lymphogenous), or monocytic; and (3) the increase or non-increase inthe number abnormal cells in the blood-leukemic or aleukemic(subleukemic). Exemplary leukemias that may be treated with a compoundor method provided herein include, for example, acute nonlymphocyticleukemia, chronic lymphocytic leukemia, acute granulocytic leukemia,chronic granulocytic leukemia, acute promyelocytic leukemia, adultT-cell leukemia, aleukemic leukemia, a leukocythemic leukemia,basophylic leukemia, blast cell leukemia, bovine leukemia, chronicmyelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilicleukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia,hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia,acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia,lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia,megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia,myeloblastic leukemia, myelocytic leukemia, myeloid granulocyticleukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cellleukemia, multiple myeloma, plasmacytic leukemia, promyelocyticleukemia, Rieder cell leukemia, Schilling's leukemia, stem cellleukemia, subleukemic leukemia, or undifferentiated cell leukemia.

The term “sarcoma” generally refers to a tumor which is made up of asubstance like the embryonic connective tissue and is generally composedof closely packed cells embedded in a fibrillar or homogeneoussubstance. Sarcomas that may be treated with a compound or methodprovided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma,melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adiposesarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma,botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma,Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing'ssarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma,granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmentedhemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma,immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma,Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymomasarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma,serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

The term “melanoma” is taken to mean a tumor arising from themelanocytic system of the skin and other organs. Melanomas that may betreated with a compound or method provided herein include, for example,acral-lentiginous melanoma, amelanotic melanoma, benign juvenilemelanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma,juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodularmelanoma, subungal melanoma, or superficial spreading melanoma.

The term “carcinoma” refers to a malignant new growth made up ofepithelial cells tending to infiltrate the surrounding tissues and giverise to metastases. Exemplary carcinomas that may be treated with acompound or method provided herein include, for example, medullarythyroid carcinoma, familial medullary thyroid carcinoma, acinarcarcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cysticcarcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolarcarcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinomabasocellulare, basaloid carcinoma, basosquamous cell carcinoma,bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogeniccarcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorioniccarcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma,cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum,cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma,carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoidcarcinoma, carcinoma epitheliale adenoides, exophytic carcinoma,carcinoma ex ulcere, carcinoma fibrosum, gelatinifori carcinoma,gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare,glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma,hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma,hyaline carcinoma, hypernephroid carcinoma, infantile embryonalcarcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelialcarcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cellcarcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatouscarcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullarycarcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma,carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma,carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes,nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans,osteoid carcinoma, papillary carcinoma, periportal carcinoma,preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma,renal cell carcinoma of kidney, reserve cell carcinoma, carcinomasarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinomascroti, signet-ring cell carcinoma, carcinoma simplex, small-cellcarcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cellcarcinoma, carcinoma spongiosum, squamous carcinoma, squamous cellcarcinoma, string carcinoma, carcinoma telangiectaticum, carcinomatelangiectodes, transitional cell carcinoma, carcinoma tuberosum,tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

A “cancer associated with aberrant Olig2 activity” (also referred toherein as “Olig2 related cancer”) is a cancer caused by aberrant Olig2activity (e.g. a mutated Olig2 gene). Olig2 related cancers may includebrain cancer, glioblastoma multiforme, medulloblastoma, astrocytomas,brain stem gliomas, meningiomas, oligodendrogliomas, melanomas, lungcancers, breast cancer, leukemias, T cell leukemias.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying causes of symptoms, inhibiting the disease or condition,e.g., arresting the development of the disease or condition, relievingthe disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically. For example, in certain methodspresented herein successfully treat cancer by decreasing the incidenceof cancer and or causing remission of cancer. In some embodiments,certain methods presented herein successfully treat Down's Syndrome bydecreasing the incidence of Down's Syndrome or reducing one or moresymptoms of Down's Syndrome or reducing the severity of one or moresymptoms of Down's Syndrome.

As used herein, amelioration of the symptoms of a particular disease,disorder or condition by administration of a particular compound orpharmaceutical composition refers to any lessening of severity, delay inonset, slowing of progression, or shortening of duration, whetherpermanent or temporary, lasting or transient that can be attributed toor associated with administration of the compound or composition.

The term “modulate,” as used herein, means to interact with a targetprotein either directly or indirectly so as to alter the activity of thetarget protein, including, by way of example only, to inhibit theactivity of the target, or to limit or reduce the activity of thetarget.

As used herein, the term “modulator” refers to a compound that alters anactivity of a target. For example, a modulator can cause an increase ordecrease in the magnitude of a certain activity of a target compared tothe magnitude of the activity in the absence of the modulator. Incertain embodiments, a modulator is an inhibitor, which decreases themagnitude of one or more activities of a target. In certain embodiments,an inhibitor completely prevents one or more activities of a target. Insome embodiments, an Olig2 modulator is a compound that reduces theactivity of Olig2 in a cell. In some embodiments, an Olig2 diseasemodulator is a compound that reduces the severity of one or moresymptoms of a disease associated with Olig2 (e.g. cancer or Down'sSyndrome).

As used herein, the term “target activity” refers to a biologicalactivity capable of being modulated by a modulator. Certain exemplarytarget activities include, but are not limited to, binding affinity,signal transduction, enzymatic activity, tumor growth, inflammation orinflammation-related processes, and amelioration of one or more symptomsassociated with a disease or condition.

The terms “inhibits”, “inhibiting”, or “inhibitor” of Olig2 activity, asused herein, refer to inhibition of oligodendrocyte transcription factor2 activity. In reference to a protein-inhibitor interaction the termsmean negatively affecting (e.g. decreasing) the activity or function ofthe protein (e.g. decreasing gene transcription regulated by Olig2)relative to the activity or function of the protein (e.g. Olig2,transcription factor) in the absence of the inhibitor (e.g. Olig2inhibitor or Olig2 inhibitor compound). In some embodiments inhibitionrefers to reduction of a disease or symptoms of disease. In someembodiments, inhibition refers to a reduction in the activity of asignal transduction pathway or signaling pathway (e.g. reduction of apathway involving transcription regulation by Olig2 or transcriptionregulated by Olig2). Thus, inhibition includes, at least in part,partially or totally blocking stimulation, decreasing, preventing, ordelaying activation, or inactivating, desensitizing, or down-regulatingsignal transduction or enzymatic activity or the amount of a protein(e.g. Olig2). In some embodiments, inhibition refers to inhibition ofOlig2.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

By “pharmaceutically acceptable,” as used herein, refers a material,such as a carrier or diluent, which does not abrogate the biologicalactivity or properties of the compound, and is relatively nontoxic,i.e., the material may be administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that one activeingredient, e.g. a compound of Formula (I), (II), (IIA), (IIB), (IIC),(IID), (III), (IV), (V) or (VI), and a co-agent, are both administeredto a patient simultaneously in the form of a single entity or dosage.The term “non-fixed combination” means that one active ingredient, e.g.a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III),(IV), (V) or (VI), and a co-agent, are administered to a patient asseparate entities either simultaneously, concurrently or sequentiallywith no specific intervening time limits, wherein such administrationprovides effective levels of the two compounds in the body of thepatient. The latter also applies to cocktail therapy, e.g. theadministration of three or more active ingredients.

The term “pharmaceutical composition” refers to a mixture of a compoundof Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or(VI) described herein with other chemical components, such as carriers,stabilizers, diluents, dispersing agents, suspending agents, thickeningagents, and/or excipients. The pharmaceutical composition facilitatesadministration of the compound to an organism. Multiple techniques ofadministering a compound exist in the art including, but not limited to:intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary andtopical administration.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition that includes a compound of Formula (I), (II), (IIA), (IIB),(IIC), (IID), (III), (IV), (V) or (VI) described herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case may be determinedusing techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules, or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated, however, the resulting reaction product can be produceddirectly from a reaction between the added reagents or from anintermediate from one or more of the added reagents which can beproduced in the reaction mixture. The term “contacting” may includeallowing two species to react, interact, or physically touch, whereinthe two species may be a compound as described herein and a protein orenzyme (e.g. Olig2). In some embodiments, the protein may be Olig2. Insome embodiments contacting includes allowing a compound describedherein to interact with a protein or enzyme that is involved intranscription.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The term “excipient” or “carrier,” as used herein, refers to relativelynontoxic chemical compounds or agents that facilitate the incorporationof a compound into cells or tissues.

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. Diluents can also be used tostabilize compounds because they can provide a more stable environment.Salts dissolved in buffered solutions (which also can provide pH controlor maintenance) are utilized as diluents in the art, including, but notlimited to a phosphate buffered saline solution.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulphydryl groups. Further information on metabolism may be obtainedfrom The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill(1996). Metabolites of the compounds disclosed herein can be identifiedeither by administration of compounds to a host and analysis of tissuesamples from the host, or by incubation of compounds with hepatic cellsin vitro and analysis of the resulting compounds.

“Bioavailability” refers to the percentage of the weight of the compounddisclosed herein (e.g. compound of Formula (I), (II), (IIA), (IIB),(IIC), (IID), (III), (IV), (V) or (VI)), that is delivered into thegeneral circulation of the animal or human being studied. The totalexposure (AUC(0-∞)) of a drug when administered intravenously is usuallydefined as 100% bioavailable (F %). “Oral bioavailability” refers to theextent to which a compound disclosed herein, is absorbed into thegeneral circulation when the pharmaceutical composition is taken orallyas compared to intravenous injection.

“Blood plasma concentration” refers to the concentration of a compoundof Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or(VI) disclosed herein, in the plasma component of blood of a subject. Itis understood that the plasma concentration of compounds describedherein may vary significantly between subjects, due to variability withrespect to metabolism and/or possible interactions with othertherapeutic agents. In accordance with one embodiment disclosed herein,the blood plasma concentration of the compounds disclosed herein mayvary from subject to subject. Likewise, values such as maximum plasmaconcentration (C max) or time to reach maximum plasma concentration (Tmax), or total area under the plasma concentration time curve (AUC(0-∞))may vary from subject to subject. Due to this variability, the amountnecessary to constitute “a therapeutically effective amount” of acompound may vary from subject to subject.

As used herein, “amelioration” refers to an improvement in a disease orcondition or at least a partial relief of symptoms associated with adisease or condition.

As used herein, “immune cells” include cells of the immune system andcells that perform a function or activity in an immune response, suchas, but not limited to, T-cells, B-cells, lymphocytes, macrophages,dendritic cells, neutrophils, eosinophils, basophils, mast cells, plasmacells, white blood cells, antigen presenting cells and natural killercells.

Treatment Methods

In another aspect is a pharmaceutical composition comprising a compoundof Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or(VI), or a pharmaceutically acceptable salt, solvate, or prodrugthereof, and at least one pharmaceutically acceptable excipient.

In another aspect is the use of a compound of Formula (I), (II), (IIA),(IIB), (IIC), (IID), (III), (IV), (V) or (VI), or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, or apharmaceutically acceptable prodrug thereof, for the formulation of amedicament for inhibiting the activity of Olig2 in a cell is provided.The method includes contacting the cell with a compound of Formula (I),(II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI), includingembodiments thereof.

Ina further aspect is a method of treating a disease, disorder orcondition in a subject that would benefit from inhibition of Olig2activity comprising administering to the subject in need thereof acomposition comprising a compound of Formula (I), (II), (IIA), (IIB),(IIC), (IID), (III), (IV), (V) or (VI), or a pharmaceutically acceptablesalt, solvate, or prodrug thereof. In some embodiments is a method oftreating a disease, disorder or condition in a subject that wouldbenefit from inhibition of Olig2 activity comprising administering tothe subject in need thereof a composition comprising a compound ofFormula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI),or a pharmaceutically acceptable salt, solvate, or prodrug thereof;wherein the disease is cancer or Down's Syndrome.

In another aspect is a method for treating a disease in a subjectcomprising administering to the subject in need thereof a compositioncomprising a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID),(III), (IV), (V) or (VI), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, wherein the disease is cancer or Down'sSyndrome. In some embodiments is a method for treating cancer in asubject comprising administering to the subject in need thereof acomposition comprising a compound of Formula (I), (II), (IIA), (IIB),(IIC), (IID), (III), (IV), (V) or (VI), or a pharmaceutically acceptablesalt, solvate, or prodrug thereof. In some embodiments is a method fortreating Down's Syndrome in a subject comprising administering to thesubject in need thereof a composition comprising a compound of Formula(I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI), or apharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment is a method for treating cancer in a subjectcomprising administering to the subject in need thereof a compositioncomprising a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID),(III), (IV), (V) or (VI), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, wherein the cancer is brain cancer,glioblastoma multiforme, medulloblastoma, astrocytomas, brain stemgliomas, meningiomas, oligodendrogliomas, melanoma, lung cancer, breastcancer, or leukemia.

In another aspect is a method of inhibiting the activity of Olig2 in acell comprising contacting the cell with a compound of Formula (I),(II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI), or apharmaceutically acceptable salt, solvate, or prodrug thereof.

In another aspect is the use of a compound of Formula (I), (II), (IIA),(IIB), (IIC), (IID), (III), (IV), (V) or (VI) or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof, in the manufacture of amedicament for the treatment of a disease, disorder, or condition thatwould benefit from inhibition of Olig2 activity.

In one aspect, provided herein is a pharmaceutical composition, whichincludes an effective amount of a compound provided herein, and apharmaceutically acceptable excipient. In a further aspect, provided arecompositions further including a second pharmaceutically activeingredient.

In certain embodiments, provided herein is a pharmaceutical compositioncontaining: i) a physiologically acceptable carrier, diluent, and/orexcipient; and ii) one or more compounds described herein.

In any of the aforementioned aspects are further embodiments thatinclude single administrations of the effective amount of the compoundsdisclosed herein, including further embodiments in which: (i) thecompound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV),(V) or (VI) is administered once; (ii) the compound of Formula (I),(II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI) isadministered to the mammal multiple times over the span of one day;(iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments thatinclude multiple administrations of the effective amount of the compoundof Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or(VI), including further embodiments in which (i) the compound of Formula(I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI) isadministered in a single dose; (ii) the time between multipleadministrations is every 6 hours; (iii) the compound of Formula (I),(II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI) isadministered to the mammal every 8 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound of Formula (I), (II), (IIA), (IIB),(IIC), (IID), (III), (IV), (V) or (VI) is temporarily suspended or thedose of the compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID),(III), (IV), (V) or (VI) being administered is temporarily reduced; atthe end of the drug holiday, dosing of the compound of Formula (I),(II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI) is resumed.The length of the drug holiday can vary from 2 days to 1 year.

In one aspect, compounds described herein are administered to a human.In some embodiments, compounds described herein are orally administered.

Examples of Pharmaceutical Compositions and Methods of Administration

Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers includingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen.Additional details about suitable excipients for pharmaceuticalcompositions described herein may be found, for example, in Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated byreference for such disclosure.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV),(V) or (VI) described herein, with other chemical components, such ascarriers, stabilizers, diluents, dispersing agents, suspending agents,thickening agents, and/or excipients. The pharmaceutical compositionfacilitates administration of the compound to an organism. In practicingthe methods of treatment or use provided herein, therapeuticallyeffective amounts of compounds described herein are administered in apharmaceutical composition to a mammal having a disease, disorder, orcondition to be treated. In some embodiments, the mammal is a human. Atherapeutically effective amount can vary widely depending on theseverity of the disease, the age and relative health of the subject, thepotency of the compound used and other factors. The compounds of Formula(I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI) can beused singly or in combination with one or more therapeutic agents ascomponents of mixtures (as in combination therapy).

The pharmaceutical formulations described herein can be administered toa subject by multiple administration routes, including but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. Moreover, the pharmaceutical compositions described herein,which include a compound of Formula (I), (II), (IIA), (IIB), (IIC),(IID), (III), (IV), (V) or (VI) described herein, can be formulated intoany suitable dosage form, including but not limited to, aqueous oraldispersions, liquids, gels, syrups, elixirs, slurries, suspensions,aerosols, controlled release formulations, fast melt formulations,effervescent formulations, lyophilized formulations, tablets, powders,pills, dragees, capsules, delayed release formulations, extended releaseformulations, pulsatile release formulations, multiparticulateformulations, and mixed immediate release and controlled releaseformulations.

One may administer the compounds and/or compositions in a local ratherthan systemic manner, for example, via injection of the compounddirectly into an organ or tissue, often in a depot preparation orsustained release formulation. Such long acting formulations may beadministered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Furthermore, one mayadminister the drug in a targeted drug delivery system, for example, ina liposome coated with organ-specific antibody. The liposomes will betargeted to and taken up selectively by the organ. In addition, the drugmay be provided in the form of a rapid release formulation, in the formof an extended release formulation, or in the form of an intermediaterelease formulation.

Pharmaceutical compositions including a compound described herein may bemanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The pharmaceutical compositions will include at least one compound ofFormula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI)described herein, as an active ingredient in free-acid or free-baseform, or in a pharmaceutically acceptable salt form. In addition, themethods and pharmaceutical compositions described herein include the useof crystalline forms (also known as polymorphs), as well as activemetabolites of these compounds having the same type of activity. In somesituations, compounds may exist as tautomers. All tautomers are includedwithin the scope of the compounds presented herein. Additionally, thecompounds described herein can exist in unsolvated as well as solvatedforms with pharmaceutically acceptable solvents such as water, ethanol,and the like. The solvated forms of the compounds presented herein arealso considered to be disclosed herein.

In certain embodiments, compositions provided herein may also includeone or more preservatives to inhibit microbial activity. Suitablepreservatives include quaternary ammonium compounds such as benzalkoniumchloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipient with one or more of the compounds describedherein (e.g. compounds of Formula (I), (II), (IIA), (IIB), (IIC), (IID),(III), (IV), (V) or (VI)), optionally grinding the resulting mixture,and processing the mixture of granules, after adding suitableauxiliaries, if desired, to obtain tablets, pills, or capsules. Suitableexcipients include, for example, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol; cellulose preparations such as,for example, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents may be added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added.

In some embodiments, the solid dosage forms disclosed herein may be inthe form of a tablet, (including a suspension tablet, a fast-melttablet, a bite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder (including a sterilepackaged powder, a dispensable powder, or an effervescent powder), acapsule (including both soft or hard capsules, e.g., capsules made fromanimal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”),solid dispersion, solid solution, bioerodible dosage form, controlledrelease formulations, pulsatile release dosage forms, multiparticulatedosage forms, pellets, granules, or an aerosol. In other embodiments,the pharmaceutical formulation is in the form of a powder. In stillother embodiments, the pharmaceutical formulation is in the form of atablet, including but not limited to, a fast-melt tablet. Additionally,pharmaceutical formulations of the compounds described herein may beadministered as a single capsule or in multiple capsule dosage form. Insome embodiments, the pharmaceutical formulation is administered in two,or three, or four, capsules or tablets.

In some embodiments, solid dosage forms, e.g., tablets, effervescenttablets, and capsules, are prepared by mixing particles of a compound ofFormula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI)described herein, with one or more pharmaceutical excipients to form abulk blend composition. When referring to these bulk blend compositionsas homogeneous, it is meant that the particles of the compound ofFormula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI)described herein, are dispersed evenly throughout the composition sothat the composition may be subdivided into equally effective unitdosage forms, such as tablets, pills, and capsules. The individual unitdosages may also include film coatings, which disintegrate upon oralingestion or upon contact with diluent. These formulations can bemanufactured by conventional pharmacological techniques.

The pharmaceutical solid dosage forms described herein can include acompound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV),(V) or (VI) described herein, and one or more pharmaceuticallyacceptable additives such as a compatible carrier, binder, fillingagent, suspending agent, flavoring agent, sweetening agent,disintegrating agent, dispersing agent, surfactant, lubricant, colorant,diluent, solubilizer, moistening agent, plasticizer, stabilizer,penetration enhancer, wetting agent, anti-foaming agent, antioxidant,preservative, or one or more combination thereof. In still otheraspects, using standard coating procedures, such as those described inRemington's Pharmaceutical Sciences, 20th Edition (2000), a film coatingis provided around the formulation of the compound described herein. Inone embodiment, some or all of the particles of the compound describedherein are coated. In another embodiment, some or all of the particlesof the compound described herein are microencapsulated. In still anotherembodiment, the particles of the compound described herein are notmicroencapsulated and are uncoated.

Suitable carriers for use in the solid dosage forms described hereininclude, but are not limited to, acacia, gelatin, colloidal silicondioxide, calcium glycerophosphate, calcium lactate, maltodextrin,glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodiumchloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyllactylate, carrageenan, monoglyceride, diglyceride, pregelatinizedstarch, hydroxypropylmethylcellulose, hydroxypropylmethylcelluloseacetate stearate, sucrose, microcrystalline cellulose, lactose, mannitoland the like.

Suitable filling agents for use in the solid dosage forms describedherein include, but are not limited to, lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, hydroxypropylmethycellulose(HPMC), hydroxypropylmethycellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose,xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethyleneglycol, and the like.

In order to release the compound of Formula (I), (II), (IIA), (IIB),(IIC), (IID), (III), (IV), (V) or (VI) from a solid dosage form matrixas efficiently as possible, disintegrants are often used in theformulation, especially when the dosage forms are compressed withbinder. Disintegrants help rupturing the dosage form matrix by swellingor capillary action when moisture is absorbed into the dosage form.Suitable disintegrants for use in the solid dosage forms describedherein include, but are not limited to, natural starch such as cornstarch or potato starch, a pregelatinized starch such as National 1551or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, acellulose such as a wood product, methylcrystalline cellulose, e.g.,Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100,Emcocel, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose,croscarmellose, or a cross-linked cellulose, such as cross-linked sodiumcarboxymethylcellulose (Ac-Di-Sol®), cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose, a cross-linkedstarch such as sodium starch glycolate, a cross-linked polymer such ascrospovidone, a cross-linked polyvinylpyrrolidone, alginate such asalginic acid or a salt of alginic acid such as sodium alginate, a claysuch as Veegum® HV (magnesium aluminum silicate), a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, a natural sponge, a surfactant, a resin such as acation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium laurylsulfate in combination starch, and the like.

Binders impart cohesiveness to solid oral dosage form formulations: forpowder filled capsule formulation, they aid in plug formation that canbe filled into soft or hard shell capsules and for tablet formulation,they ensure the tablet remaining intact after compression and helpassure blend uniformity prior to a compression or fill step. Materialssuitable for use as binders in the solid dosage forms described hereininclude, but are not limited to, carboxymethylcellulose, methylcellulose(e.g., Methocel®), hydroxypropylmethylcellulose (e.g. Hypromellose USPPharmacoat-603, hydroxypropylmethylcellulose acetate stearate (AgoateHS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g.,Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystallinecellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesiumaluminum silicate, polysaccharide acids, bentonites, gelatin,polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone,starch, pregelatinized starch, tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such asacacia, tragacanth, ghatti gum, mucilage of isapol husks, starch,polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone®XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethyleneglycol, waxes, sodium alginate, and the like.

In general, binder levels of 20-70% are used in powder-filled gelatincapsule formulations. Binder usage level in tablet formulations varieswhether direct compression, wet granulation, roller compaction, or usageof other excipients such as fillers which itself can act as moderatebinder. In some embodiments, formulators determine the binder level forthe formulations, but binder usage level of up to 70% in tabletformulations is common.

Suitable lubricants or glidants for use in the solid dosage formsdescribed herein include, but are not limited to, stearic acid, calciumhydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal andalkaline earth metal salts, such as aluminum, calcium, magnesium, zinc,stearic acid, sodium stearates, magnesium stearate, zinc stearate,waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol or a methoxypolyethylene glycolsuch as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol,sodium oleate, glyceryl behenate, glyceryl palmitostearate, glycerylbenzoate, magnesium or sodium lauryl sulfate, and the like.

Suitable diluents for use in the solid dosage forms described hereininclude, but are not limited to, sugars (including lactose, sucrose, anddextrose), polysaccharides (including dextrates and maltodextrin),polyols (including mannitol, xylitol, and sorbitol), cyclodextrins andthe like.

Suitable wetting agents for use in the solid dosage forms describedherein include, for example, oleic acid, glyceryl monostearate, sorbitanmonooleate, sorbitan monolaurate, triethanolamine oleate,polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodiumoleate, sodium lauryl sulfate, magnesium stearate, sodium docusate,triacetin, vitamin E TPGS and the like.

Suitable surfactants for use in the solid dosage forms described hereininclude, for example, sodium lauryl sulfate, sorbitan monooleate,polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bilesalts, glyceryl monostearate, copolymers of ethylene oxide and propyleneoxide, e.g., Pluronic® (BASF), and the like.

Suitable suspending agents for use in the solid dosage forms describedhere include, but are not limited to, polyvinylpyrrolidone, e.g.,polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., thepolyethylene glycol can have a molecular weight of about 300 to about6000, or about 3350 to about 4000, or about 5400 to about 7000, vinylpyrrolidone/vinyl acetate copolymer (S630), sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

Suitable antioxidants for use in the solid dosage forms described hereininclude, for example, e.g., butylated hydroxytoluene (BHT), sodiumascorbate, and tocopherol.

There is considerable overlap between additives used in the solid dosageforms described herein. Thus, the above-listed additives should be takenas merely exemplary, and not limiting, of the types of additives thatcan be included in solid dosage forms of the pharmaceutical compositionsdescribed herein.

In other embodiments, one or more layers of the pharmaceuticalformulation are plasticized. Illustratively, a plasticizer is generallya high boiling point solid or liquid. Suitable plasticizers can be addedfrom about 0.01% to about 50% by weight (w/w) of the coatingcomposition. Plasticizers include, but are not limited to, diethylphthalate, citrate esters, polyethylene glycol, glycerol, acetylatedglycerides, triacetin, polypropylene glycol, polyethylene glycol,triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, andcastor oil.

Compressed tablets are solid dosage forms prepared by compacting thebulk blend of the formulations described above. In various embodiments,compressed tablets which are designed to dissolve in the mouth willinclude one or more flavoring agents. In other embodiments, thecompressed tablets will include a film surrounding the final compressedtablet. In some embodiments, the film coating can provide a delayedrelease of the compounds of Formula (I), (II), (IIA), (IIB), (IIC),(IID), (III), (IV), (V) or (VI) described herein from the formulation.In other embodiments, the film coating aids in patient compliance (e.g.,Opadry® coatings or sugar coating). Film coatings including Opadry®typically range from about 1% to about 3% of the tablet weight. In otherembodiments, the compressed tablets include one or more excipients.

A capsule may be prepared, for example, by placing the bulk blend of theformulation of the compound described above, inside of a capsule. Insome embodiments, the formulations (non-aqueous suspensions andsolutions) are placed in a soft gelatin capsule. In other embodiments,the formulations are placed in standard gelatin capsules or non-gelatincapsules such as capsules comprising HPMC. In other embodiments, theformulation is placed in a sprinkle capsule, wherein the capsule may beswallowed whole or the capsule may be opened and the contents sprinkledon food prior to eating. In some embodiments, the therapeutic dose issplit into multiple (e.g., two, three, or four) capsules. In someembodiments, the entire dose of the formulation is delivered in acapsule form.

In various embodiments, the particles of the compound of Formula (I),(II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI) describedherein and one or more excipients are dry blended and compressed into amass, such as a tablet, having a hardness sufficient to provide apharmaceutical composition that substantially disintegrates within lessthan about 30 minutes, less than about 35 minutes, less than about 40minutes, less than about 45 minutes, less than about 50 minutes, lessthan about 55 minutes, or less than about 60 minutes, after oraladministration, thereby releasing the formulation into thegastrointestinal fluid.

In another aspect, dosage forms may include microencapsulatedformulations. In some embodiments, one or more other compatiblematerials are present in the microencapsulation material. Exemplarymaterials include, but are not limited to, pH modifiers, erosionfacilitators, anti-foaming agents, antioxidants, flavoring agents, andcarrier materials such as binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, and diluents.

Materials useful for the microencapsulation described herein includematerials compatible with compounds described herein, which sufficientlyisolate the compound from other non-compatible excipients. Materialscompatible with compounds described herein are those that delay therelease of the compounds of Formula (I), (II), (IIA), (IIB), (IIC),(IID), (III), (IV), (V) or (VI) in vivo.

Exemplary microencapsulation materials useful for delaying the releaseof the formulations including compounds described herein, include, butare not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel®or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC),hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC,Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, BenecelMP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A,hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS) and Metolose®, Ethylcelluloses (EC) and mixtures thereof such asE461, Ethocel®, Aqualon®-EC, Surelease®, Polyvinyl alcohol (PVA) such asOpadry AMB, hydroxyethylcelluloses such as Natrosol®,carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) suchas Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol co-polymerssuch as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX),polyethylene glycols, modified food starch, acrylic polymers andmixtures of acrylic polymers with cellulose ethers such as Eudragit®EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit®L100, Eudragit® 5100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5,Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, celluloseacetate phthalate, sepifilms such as mixtures of HPMC and stearic acid,cyclodextrins, and mixtures of these materials.

In still other embodiments, plasticizers such as polyethylene glycols,e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800,stearic acid, propylene glycol, oleic acid, and triacetin areincorporated into the microencapsulation material. In other embodiments,the microencapsulating material useful for delaying the release of thepharmaceutical compositions is from the USP or the National Formulary(NF). In yet other embodiments, the microencapsulation material isKlucel. In still other embodiments, the microencapsulation material ismethocel.

Microencapsulated compounds described herein may be formulated bymethods that include, e.g., spray drying processes, spinningdisk-solvent processes, hot melt processes, spray chilling methods,fluidized bed, electrostatic deposition, centrifugal extrusion,rotational suspension separation, polymerization at liquid-gas orsolid-gas interface, pressure extrusion, or spraying solvent extractionbath. In addition to these, several chemical techniques, e.g., complexcoacervation, solvent evaporation, polymer-polymer incompatibility,interfacial polymerization in liquid media, in situ polymerization,in-liquid drying, and desolvation in liquid media could also be used.Furthermore, other methods such as roller compaction,extrusion/spheronization, coacervation, or nanoparticle coating may alsobe used.

In still other embodiments, effervescent powders are also prepared inaccordance with the present disclosure. Effervescent salts have beenused to disperse medicines in water for oral administration.Effervescent salts are granules or coarse powders containing a medicinalagent in a dry mixture, usually composed of sodium bicarbonate, citricacid and/or tartaric acid. When such salts are added to water, the acidsand the base react to liberate carbon dioxide gas, thereby causing“effervescence.” Examples of effervescent salts include, e.g., thefollowing ingredients: sodium bicarbonate or a mixture of sodiumbicarbonate and sodium carbonate, citric acid and/or tartaric acid. Anyacid-base combination that results in the liberation of carbon dioxidecan be used in place of the combination of sodium bicarbonate and citricand tartaric acids, as long as the ingredients were suitable forpharmaceutical use and result in a pH of about 6.0 or higher.

In other embodiments, the formulations described herein, which include acompound described herein, are solid dispersions. Methods of producingsuch solid dispersions include, but are not limited to, for example,U.S. Pat. Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269,and U.S. patent publication no. 2004/0013734. In still otherembodiments, the formulations described herein are solid solutions.Solid solutions incorporate a substance together with the active agentand other excipients such that heating the mixture results indissolution of the drug and the resulting composition is then cooled toprovide a solid blend which can be further formulated or directly addedto a capsule or compressed into a tablet. Methods of producing suchsolid solutions include, but are not limited to, for example, U.S. Pat.Nos. 4,151,273, 5,281,420, and 6,083,518.

The pharmaceutical solid oral dosage forms including formulationsdescribed herein, which include a compounds described herein, can befurther formulated to provide a controlled release of the compound ofFormula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI).Controlled release refers to the release of the compounds describedherein from a dosage form in which it is incorporated according to adesired profile over an extended period of time. Controlled releaseprofiles include, for example, sustained release, prolonged release,pulsatile release, and delayed release profiles. In contrast toimmediate release compositions, controlled release compositions allowdelivery of an agent to a subject over an extended period of timeaccording to a predetermined profile. Such release rates can providetherapeutically effective levels of agent for an extended period of timeand thereby provide a longer period of pharmacologic response whileminimizing side effects as compared to conventional rapid release dosageforms. Such longer periods of response provide for many inherentbenefits that are not achieved with the corresponding short acting,immediate release preparations.

In some embodiments, the solid dosage forms described herein can beformulated as enteric coated delayed release oral dosage forms, i.e., asan oral dosage form of a pharmaceutical composition as described hereinwhich utilizes an enteric coating to affect release in the smallintestine of the gastrointestinal tract. The enteric coated dosage formmay be a compressed or molded or extruded tablet/mold (coated oruncoated) containing granules, powder, pellets, beads or particles ofthe active ingredient and/or other composition components, which arethemselves coated or uncoated. The enteric coated oral dosage form mayalso be a capsule (coated or uncoated) containing pellets, beads orgranules of the solid carrier or the composition, which are themselvescoated or uncoated.

The term “delayed release” as used herein refers to the delivery so thatthe release can be accomplished at some generally predictable locationin the intestinal tract more distal to that which would have beenaccomplished if there had been no delayed release alterations. In someembodiments the method for delay of release is coating. Any coatingsshould be applied to a sufficient thickness such that the entire coatingdoes not dissolve in the gastrointestinal fluids at pH below about 5,but does dissolve at pH about 5 and above. Coatings may be made from:

Acrylic polymers. The performance of acrylic polymers (primarily theirsolubility in biological fluids) can vary based on the degree and typeof substitution. Examples of suitable acrylic polymers includemethacrylic acid copolymers and ammonium methacrylate copolymers. TheEudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available assolubilized in organic solvent, aqueous dispersion, or dry powders. TheEudragit series RL, NE, and RS are insoluble in the gastrointestinaltract but are permeable and are used primarily for colonic targeting.The Eudragit series E dissolve in the stomach. The Eudragit series L,L-30D and S are insoluble in stomach and dissolve in the intestine;

Cellulose Derivatives. Examples of suitable cellulose derivatives are:ethyl cellulose; reaction mixtures of partial acetate esters ofcellulose with phthalic anhydride. The performance can vary based on thedegree and type of substitution. Cellulose acetate phthalate (CAP)dissolves in pH >6. Aquateric (FMC) is an aqueous based system and is aspray dried CAP pseudolatex with particles <1 μm. Other components inAquateric can include pluronics, Tweens, and acetylated monoglycerides.Other suitable cellulose derivatives include: cellulose acetatetrimellitate (Eastman); methylcellulose (Pharmacoat, Methocel);hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethylcellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetatesuccinate (e.g., AQOAT (Shin Etsu)). The performance can vary based onthe degree and type of substitution. For example, HPMCP such as, HP-50,HP-55, HP-55S, HP-55F grades are suitable. The performance can varybased on the degree and type of substitution. For example, suitablegrades of hydroxypropylmethylcellulose acetate succinate include, butare not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF),which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH.These polymers are offered as granules, or as fine powders for aqueousdispersions;

Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in pH >5, and it ismuch less permeable to water vapor and gastric fluids.

In some embodiments, the coating can, and usually does, contain aplasticizer and possibly other coating excipients such as colorants,talc, and/or magnesium stearate. Suitable plasticizers include triethylcitrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethylcitrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethylphthalate, tributyl citrate, acetylated monoglycerides, glycerol, fattyacid esters, propylene glycol, and dibutyl phthalate. In particular,anionic carboxylic acrylic polymers usually will contain 10-25% byweight of a plasticizer, especially dibutyl phthalate, polyethyleneglycol, triethyl citrate and triacetin. Conventional coating techniquessuch as spray or pan coating are employed to apply coatings. The coatingthickness must be sufficient to ensure that the oral dosage form remainsintact until the desired site of topical delivery in the intestinaltract is reached.

Colorants, detackifiers, surfactants, antifoaming agents, lubricants(e.g., carnuba wax or PEG) may be added to the coatings besidesplasticizers to solubilize or disperse the coating material, and toimprove coating performance and the coated product.

In other embodiments, the formulations described herein, which include acompound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV),(V) or (VI) described herein, are delivered using a pulsatile dosageform. A pulsatile dosage form is capable of providing one or moreimmediate release pulses at predetermined time points after a controlledlag time or at specific sites. Pulsatile dosage forms may beadministered using a variety of pulsatile formulations including, butare not limited to, those described in U.S. Pat. Nos. 5,011,692;5,017,381; 5,229,135; 5,840,329; 4,871,549; 5,260,068; 5,260,069;5,508,040; 5,567,441 and 5,837,284.

Many other types of controlled release systems are suitable for use withthe formulations described herein. Examples of such delivery systemsinclude, e.g., polymer-based systems, such as polylactic andpolyglycolic acid, polyanhydrides and polycaprolactone; porous matrices,nonpolymer-based systems that are lipids, including sterols, such ascholesterol, cholesterol esters and fatty acids, or neutral fats, suchas mono-, di- and triglycerides; hydrogel release systems; silasticsystems; peptide-based systems; wax coatings, bioerodible dosage forms,compressed tablets using conventional binders and the like. See, e.g.,Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214(1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2ndEd., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725; 4,624,848; 4,968,509;5,461,140; 5,456,923; 5,516,527; 5,622,721; 5,686,105; 5,700,410;5,977,175; 6,465,014; and 6,932,983.

In some embodiments, pharmaceutical formulations are provided thatinclude particles of the compounds described herein, e.g. compounds ofFormula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI),and at least one dispersing agent or suspending agent for oraladministration to a subject. The formulations may be a powder and/orgranules for suspension, and upon admixture with water, a substantiallyuniform suspension is obtained.

Liquid formulation dosage forms for oral administration can be aqueoussuspensions selected from the group including, but not limited to,pharmaceutically acceptable aqueous oral dispersions, emulsions,solutions, elixirs, gels, and syrups. See, e.g., Singh et al.,Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).

The aqueous suspensions and dispersions described herein can remain in ahomogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005edition, chapter 905), for at least 4 hours. The homogeneity should bedetermined by a sampling method consistent with regard to determininghomogeneity of the entire composition. In one embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 1 minute. In another embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 45 seconds. In yet another embodiment, anaqueous suspension can be re-suspended into a homogenous suspension byphysical agitation lasting less than 30 seconds. In still anotherembodiment, no agitation is necessary to maintain a homogeneous aqueousdispersion.

The pharmaceutical compositions described herein may include sweeteningagents such as, but not limited to, acacia syrup, acesulfame K, alitame,anise, apple, aspartame, banana, Bavarian cream, berry, black currant,butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream,chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream,cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate,cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger,glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey,isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate(MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mintcream, mixed berry, neohesperidine DC, neotame, orange, pear, peach,peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer,rum, saccharin, safrole, sorbitol, spearmint, spearmint cream,strawberry, strawberry cream, stevia, sucralose, sucrose, sodiumsaccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin,sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tuttifruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol,or any combination of these flavoring ingredients, e.g., anise-menthol,cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint,honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream,vanilla-mint, and mixtures thereof.

In some embodiments, the pharmaceutical formulations described hereincan be self-emulsifying drug delivery systems (SEDDS). Emulsions aredispersions of one immiscible phase in another, usually in the form ofdroplets. Generally, emulsions are created by vigorous mechanicaldispersion. SEDDS, as opposed to emulsions or microemulsions,spontaneously form emulsions when added to an excess of water withoutany external mechanical dispersion or agitation. An advantage of SEDDSis that only gentle mixing is required to distribute the dropletsthroughout the solution. Additionally, water or the aqueous phase can beadded just prior to administration, which ensures stability of anunstable or hydrophobic active ingredient. Thus, the SEDDS provides aneffective delivery system for oral and parenteral delivery ofhydrophobic active ingredients. SEDDS may provide improvements in thebioavailability of hydrophobic active ingredients. Methods of producingself-emulsifying dosage forms include, but are not limited to, forexample, U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563.

There is overlap between the above-listed additives used in the aqueousdispersions or suspensions described herein, since a given additive isoften classified differently by different practitioners in the field, oris commonly used for any of several different functions. Thus, theabove-listed additives should be taken as merely exemplary, and notlimiting, of the types of additives that can be included in formulationsdescribed herein.

Potential excipients for intranasal formulations include, for example,U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452. Formulationssolutions in saline, employing benzyl alcohol or other suitablepreservatives, fluorocarbons, and/or other solubilizing or dispersingagents. See, for example, Ansel, H. C. et al., Pharmaceutical DosageForms and Drug Delivery Systems, Sixth Ed. (1995). Preferably thesecompositions and formulations are prepared with suitable nontoxicpharmaceutically acceptable ingredients. The choice of suitable carriersis highly dependent upon the exact nature of the nasal dosage formdesired, e.g., solutions, suspensions, ointments, or gels. Nasal dosageforms generally contain large amounts of water in addition to the activeingredient. Minor amounts of other ingredients such as pH adjusters,emulsifiers or dispersing agents, preservatives, surfactants, gellingagents, or buffering and other stabilizing and solubilizing agents mayalso be present. Preferably, the nasal dosage form should be isotonicwith nasal secretions.

For administration by inhalation, the compounds described herein may bein a form as an aerosol, a mist or a powder. Pharmaceutical compositionsdescribed herein are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, such as, by way of example only, gelatin foruse in an inhaler or insufflator may be formulated containing a powdermix of the compound described herein and a suitable powder base such aslactose or starch.

Buccal formulations that include compounds described herein may beadministered using a variety of formulations which include, but are notlimited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and5,739,136. In addition, the buccal dosage forms described herein canfurther include a bioerodible (hydrolysable) polymeric carrier that alsoserves to adhere the dosage form to the buccal mucosa. The buccal dosageform is fabricated so as to erode gradually over a predetermined timeperiod, wherein the delivery of the compound is provided essentiallythroughout. Buccal drug delivery avoids the disadvantages encounteredwith oral drug administration, e.g., slow absorption, degradation of theactive agent by fluids present in the gastrointestinal tract and/orfirst-pass inactivation in the liver. With regard to the bioerodible(hydrolysable) polymeric carrier, virtually any such carrier can beused, so long as the desired drug release profile is not compromised,and the carrier is compatible with the compounds described herein, andany other components that may be present in the buccal dosage unit.Generally, the polymeric carrier comprises hydrophilic (water-solubleand water-swellable) polymers that adhere to the wet surface of thebuccal mucosa. Examples of polymeric carriers useful herein includeacrylic acid polymers and co, e.g., those known as “carbomers”(Carbopol®, which may be obtained from B.F. Goodrich, is one suchpolymer). Other components may also be incorporated into the buccaldosage forms described herein include, but are not limited to,disintegrants, diluents, binders, lubricants, flavoring, colorants,preservatives, and the like. For buccal or sublingual administration,the compositions may take the form of tablets, lozenges, or gelsformulated in a conventional manner.

Transdermal formulations described herein may be administered using avariety of devices including but not limited to, U.S. Pat. Nos.3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097,3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894,4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299,4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983,6,929,801 and 6,946,144.

The transdermal dosage forms described herein may incorporate certainpharmaceutically acceptable excipients which are conventional in theart. In one embodiment, the transdermal formulations described hereininclude at least three components: (1) a formulation of a compound of,(2) a penetration enhancer; and (3) an aqueous adjuvant. In addition,transdermal formulations can include additional components such as, butnot limited to, gelling agents, creams and ointment bases, and the like.In some embodiments, the transdermal formulation can further include awoven or non-woven backing material to enhance absorption and preventthe removal of the transdermal formulation from the skin. In otherembodiments, the transdermal formulations described herein can maintaina saturated or supersaturated state to promote diffusion into the skin.

Formulations suitable for transdermal administration of compoundsdescribed herein may employ transdermal delivery devices and transdermaldelivery patches and can be lipophilic emulsions or buffered, aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive. Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents. Still further, transdermal deliveryof the compounds described herein can be accomplished by means ofiontophoretic patches and the like. Additionally, transdermal patchescan provide controlled delivery of the compounds described herein. Therate of absorption can be slowed by using rate-controlling membranes orby trapping the compound within a polymer matrix or gel. Conversely,absorption enhancers can be used to increase absorption. An absorptionenhancer or carrier can include absorbable pharmaceutically acceptablesolvents to assist passage through the skin. For example, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound to the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

Formulations suitable for intramuscular, subcutaneous, or intravenousinjection may include physiologically acceptable sterile aqueous ornon-aqueous solutions, dispersions, suspensions or emulsions, andsterile powders for reconstitution into sterile injectable solutions ordispersions. Examples of suitable aqueous and non-aqueous carriers,diluents, solvents, or vehicles including water, ethanol, polyols(propyleneglycol, polyethylene-glycol, glycerol, cremophor and thelike), suitable mixtures thereof, vegetable oils (such as olive oil) andinjectable organic esters such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case ofdispersions, and by the use of surfactants. Formulations suitable forsubcutaneous injection may also contain additives such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the growth ofmicroorganisms can be ensured by various antibacterial and antifungalagents, such as parabens, chlorobutanol, phenol, sorbic acid, and thelike. It may also be desirable to include isotonic agents, such assugars, sodium chloride, and the like. Prolonged absorption of theinjectable pharmaceutical form can be brought about by the use of agentsdelaying absorption, such as aluminum monostearate and gelatin.

For intravenous injections, compounds described herein may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally recognized in the field. For other parenteral injections,appropriate formulations may include aqueous or nonaqueous solutions,preferably with physiologically compatible buffers or excipients. Suchexcipients are generally recognized in the field.

Parenteral injections may involve bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The pharmaceutical composition described herein may be ina form suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Pharmaceutical formulations for parenteral administrationinclude aqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

In certain embodiments, delivery systems for pharmaceutical compoundsmay be employed, such as, for example, liposomes and emulsions. Incertain embodiments, compositions provided herein also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

In some embodiments, the compounds described herein may be administeredtopically and are formulated into a variety of topically administrablecompositions, such as solutions, suspensions, lotions, gels, pastes,medicated sticks, balms, creams or ointments. Such pharmaceuticalcompounds can contain solubilizers, stabilizers, tonicity enhancingagents, buffers and preservatives.

The compounds described herein may also be formulated in rectalcompositions such as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas, containingconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and thelike. In suppository forms of the compositions, a low-melting wax suchas, but not limited to, a mixture of fatty acid glycerides, optionallyin combination with cocoa butter is first melted.

Generally, an agent, such as a compound of Formula (I), (II), (IIA),(IIB), (IIC), (IID), (III), (IV), (V) or (VI), is administered in anamount effective for amelioration of, or prevention of the developmentof symptoms of, the disease or disorder (i.e., a therapeuticallyeffective amount). Thus, a therapeutically effective amount can be anamount that is capable of at least partially preventing or reversing adisease or disorder. The dose required to obtain an effective amount mayvary depending on the agent, formulation, disease or disorder, andindividual to whom the agent is administered.

Determination of effective amounts may also involve in vitro assays inwhich varying doses of agent are administered to cells in culture andthe concentration of agent effective for ameliorating some or allsymptoms is determined in order to calculate the concentration requiredin vivo. Effective amounts may also be based in in vivo animal studies.

An agent can be administered prior to, concurrently with and subsequentto the appearance of symptoms of a disease or disorder. In someembodiments, an agent is administered to a subject with a family historyof the disease or disorder, or who has a phenotype that may indicate apredisposition to a disease or disorder, or who has a genotype whichpredisposes the subject to the disease or disorder.

Examples of Methods of Dosing and Treatment Regimens

The compounds described herein can be used in the preparation ofmedicaments for the treatment of cancer, or for the treatment ofdiseases or conditions that would benefit, at least in part, from Olig2inhibition. In addition, a method for treating any of the diseases orconditions described herein in a subject in need of such treatment,involves administration of pharmaceutical compositions containing atleast one compound described herein, or a pharmaceutically acceptablesalt, pharmaceutically acceptable prodrug, or pharmaceuticallyacceptable solvate thereof, in therapeutically effective amounts to saidsubject.

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or365 days. The dose reduction during a drug holiday may be from about 10%to about 100%, including, by way of example only, about 10%, about 15%,about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,about 85%, about 90%, about 95%, or about 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, disease orcondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be determined in amanner recognized in the field according to the particular circumstancessurrounding the case, including, e.g., the specific agent beingadministered, the route of administration, the condition being treated,and the subject or host being treated. In general, however, dosesemployed for adult human treatment will typically be in the range ofabout 0.02-about 5000 mg per day, in some embodiments, about 1-about1500 mg per day. The desired dose may conveniently be presented in asingle dose or as divided doses administered simultaneously (or over ashort period of time) or at appropriate intervals, for example as two,three, four or more sub-doses per day.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

The daily dosages appropriate for the compounds described hereindescribed herein are from about 0.01 mg/kg to about 20 mg/kg. In oneembodiment, the daily dosages are from about 0.1 mg/kg to about 10mg/kg. An indicated daily dosage in the larger mammal, including, butnot limited to, humans, is in the range from about 0.5 mg to about 1000mg, conveniently administered in a single dose or in divided doses,including, but not limited to, up to four times a day or in extendedrelease form. Suitable unit dosage forms for oral administration includefrom about 1 to about 500 mg active ingredient. In one embodiment, theunit dosage is about 1 mg, about 5 mg, about, 10 mg, about 20 mg, about50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg, or about500 mg. The foregoing ranges are merely suggestive, as the number ofvariables in regard to an individual treatment regime is large, andconsiderable excursions from these recommended values are not uncommon.Such dosages may be altered depending on a number of variables, notlimited to the activity of the compound used, the disease or conditionto be treated, the mode of administration, the requirements of theindividual subject, the severity of the disease or condition beingtreated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

Combination Treatments

The compounds of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III),(IV), (V) or (VI), and compositions thereof, may also be used incombination with other therapeutic agents that are selected for theirtherapeutic value for the condition to be treated. In general, thecompositions described herein and, in embodiments where combinationaltherapy is employed, other agents do not have to be administered in thesame pharmaceutical composition, and may, because of different physicaland chemical characteristics, have to be administered by differentroutes. The determination of the mode of administration and theadvisability of administration, where possible, in the samepharmaceutical composition, is well within the knowledge of theclinician. The initial administration can be made according toestablished protocols recognized in the field, and then, based upon theobserved effects, the dosage, modes of administration and times ofadministration can be modified by the clinician.

In certain instances, it may be appropriate to administer at least onecompound described herein in combination with another therapeutic agent.By way of example only, if one of the side effects experienced by apatient upon receiving one of the compounds herein, such as a compoundof Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or(VI), is nausea, then it may be appropriate to administer an anti-nauseaagent in combination with the initial therapeutic agent. Or, by way ofexample only, the therapeutic effectiveness of one of the compoundsdescribed herein may be enhanced by administration of an adjuvant (i.e.,by itself the adjuvant may have minimal therapeutic benefit, but incombination with another therapeutic agent, the overall therapeuticbenefit to the patient is enhanced). Or, by way of example only, thebenefit experienced by a patient may be increased by administering oneof the compounds described herein with another therapeutic agent (whichalso includes a therapeutic regimen) that also has therapeutic benefit.In any case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient may simply beadditive of the two therapeutic agents or the patient may experience asynergistic benefit.

For therapeutic applications, the compounds or drugs of the presentinvention can be administered alone or co-administered in combinationwith conventional chemotherapy, radiotherapy, hormonal therapy, and/orimmunotherapy.

As a non-limiting example, the compounds of Formula (I), (II), (IIA),(IIB), (IIC), (IID), (III), (IV), (V) or (VI) described herein can beco-administered with conventional chemotherapeutic agents includingalkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil,busulfan, melphalan, mechlorethamine, uramustine, thiotepa,nitrosoureas, etc.), anti-metabolites (e.g., 5-fluorouracil,azathioprine, methotrexate, leucovorin, capecitabine, cytarabine,floxuridine, fludarabine, gemcitabine, pemetrexed, raltitrexed, etc.),plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine,podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors(e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposidephosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin,adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin,mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g.cisplatin, oxaloplatin, carboplatin, etc.), and the like.

The compounds of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III),(IV), (V) or (VI) described herein can also be co-administered withconventional hormonal therapeutic agents including, but not limited to,steroids (e.g., dexamethasone), finasteride, aromatase inhibitors,tamoxifen, and gonadotropin-releasing hormone agonists (GnRH) such asgoserelin.

Additionally, the compounds of Formula (I), (II), (IIA), (IIB), (IIC),(IID), (III), (IV), (V) or (VI) described herein can be co-administeredwith conventional immunotherapeutic agents including, but not limitedto, immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole,interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g.,anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonalantibodies), immunotoxins (e.g., anti-CD33 monoclonalantibody-calicheamicin conjugate, anti-CD22 monoclonalantibody-pseudomonas exotoxin conjugate, etc.), and radioimmunotherapy(e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I,etc.).

In further embodiments, the compounds of Formula (I), (II), (IIA),(IIB), (IIC), (IID), (III), (IV), (V) or (VI) described herein can alsobe co-administered with STAT 3 inhibitors or Janus Kinase inhibitors.

The particular choice of compounds used will depend upon the diagnosisof the attending physicians and their judgment of the condition of thepatient and the appropriate treatment protocol. The compounds may beadministered concurrently (e.g., simultaneously, essentiallysimultaneously or within the same treatment protocol) or sequentially,depending upon the nature of the disease, disorder, or condition, thecondition of the patient, and the actual choice of compounds used. Thedetermination of the order of administration, and the number ofrepetitions of administration of each therapeutic agent during atreatment protocol, is well within the knowledge of the physician afterevaluation of the disease being treated and the condition of thepatient.

Therapeutically-effective dosages can vary when the drugs are used intreatment combinations. Methods for experimentally determiningtherapeutically-effective dosages of drugs and other agents for use incombination treatment regimens are described in the literature. Forexample, the use of metronomic dosing, i.e., providing more frequent,lower doses in order to minimize toxic side effects, has been describedextensively in the literature Combination treatment further includesperiodic treatments that start and stop at various times to assist withthe clinical management of the patient.

For combination therapies described herein, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the disease orcondition being treated and so forth. In addition, when co-administeredwith one or more biologically active agents, the compound providedherein may be administered either simultaneously with the biologicallyactive agent(s), or sequentially. If administered sequentially, theattending physician will decide on the appropriate sequence ofadministering protein in combination with the biologically activeagent(s).

In any case, the multiple therapeutic agents (one of which is a compoundof Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or(VI) described herein) may be administered in any order or evensimultaneously. If simultaneously, the multiple therapeutic agents maybe provided in a single, unified form, or in multiple forms (by way ofexample only, either as a single pill or as two separate pills). One ofthe therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may vary from more than zero weeks to less than fourweeks. In addition, the combination methods, compositions andformulations are not to be limited to the use of only two agents; theuse of multiple therapeutic combinations are also envisioned.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, can be modifiedin accordance with a variety of factors. These factors include thedisorder or condition from which the subject suffers, as well as theage, weight, sex, diet, and medical condition of the subject. Thus, thedosage regimen actually employed can vary widely and therefore candeviate from the dosage regimens set forth herein.

The pharmaceutical agents which make up the combination therapydisclosed herein may be a combined dosage form or in separate dosageforms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy may also beadministered sequentially, with either therapeutic compound beingadministered by a regimen calling for two-step administration. Thetwo-step administration regimen may call for sequential administrationof the active agents or spaced-apart administration of the separateactive agents. The time period between the multiple administration stepsmay range from, a few minutes to several hours, depending upon theproperties of each pharmaceutical agent, such as potency, solubility,bioavailability, plasma half-life and kinetic profile of thepharmaceutical agent. Circadian variation of the target moleculeconcentration may also determine the optimal dose interval.

In addition, the compounds described herein also may be used incombination with procedures that may provide additional or synergisticbenefit to the patient. By way of example only, patients are expected tofind therapeutic and/or prophylactic benefit in the methods describedherein, wherein pharmaceutical composition of a compound disclosedherein and/or combinations with other therapeutics are combined withgenetic testing to determine whether that individual is a carrier of amutant gene that is known to be correlated with certain diseases orconditions.

The compounds described herein and combination therapies can beadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the composition containing acompound can vary. Thus, for example, the compounds can be used as aprophylactic and can be administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. The compounds and compositionscan be administered to a subject during or as soon as possible after theonset of the symptoms. The administration of the compounds can beinitiated within the first 48 hours of the onset of the symptoms,preferably within the first 48 hours of the onset of the symptoms, morepreferably within the first 6 hours of the onset of the symptoms, andmost preferably within 3 hours of the onset of the symptoms. The initialadministration can be via any route practical, such as, for example, anintravenous injection, a bolus injection, infusion over about 5 minutesto about 5 hours, a pill, a capsule, transdermal patch, buccal delivery,and the like, or combination thereof. A compound is preferablyadministered as soon as is practicable after the onset of a disease orcondition is detected or suspected, and for a length of time necessaryfor the treatment of the disease, such as, for example, from 1 day toabout 3 months. The length of treatment can vary for each subject, andthe length can be determined using the known criteria. For example, thecompound or a formulation containing the compound can be administeredfor at least 2 weeks, preferably about 1 month to about 5 years.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also described herein. Such kits can includea carrier, package, or container that is compartmentalized to receiveone or more containers such as vials, tubes, and the like, each of thecontainer(s) including one of the separate elements to be used in amethod described herein. Suitable containers include, for example,bottles, vials, syringes, and test tubes. The containers can be formedfrom a variety of materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical productsinclude, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, bottles, and any packaging material suitable for aselected formulation and intended mode of administration and treatment.A wide array of formulations of the compounds and compositions providedherein are contemplated as are a variety of treatments for any disease,disorder, or condition that would benefit by inhibition of Olig2activity.

For example, the container(s) can include one or more compoundsdescribed herein, optionally in a composition or in combination withanother agent as disclosed herein. The container(s) optionally have asterile access port (for example the container can be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). Such kits optionally comprising a compound with anidentifying description or label or instructions relating to its use inthe methods described herein.

A kit will typically may include one or more additional containers, eachwith one or more of various materials (such as reagents, optionally inconcentrated form, and/or devices) desirable from a commercial and userstandpoint for use of a compound described herein. Non-limiting examplesof such materials include, but not limited to, buffers, diluents,filters, needles, syringes; carrier, package, container, vial and/ortube labels listing contents and/or instructions for use, and packageinserts with instructions for use. A set of instructions will alsotypically be included.

A label can be on or associated with the container. A label can be on acontainer when letters, numbers or other characters forming the labelare attached, molded or etched into the container itself, a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Alabel can be used to indicate that the contents are to be used for aspecific therapeutic application. The label can also indicate directionsfor use of the contents, such as in the methods described herein.

In certain embodiments, the pharmaceutical compositions can be presentedin a pack or dispenser device which can contain one or more unit dosageforms containing a compound provided herein. The pack can for examplecontain metal or plastic foil, such as a blister pack. The pack ordispenser device can be accompanied by instructions for administration.The pack or dispenser can also be accompanied with a notice associatedwith the container in form prescribed by a governmental agencyregulating the manufacture, use, or sale of pharmaceuticals, whichnotice is reflective of approval by the agency of the form of the drugfor human or veterinary administration. Such notice, for example, can bethe labeling approved by the U.S. Food and Drug Administration forprescription drugs, or the approved product insert. Compositionscontaining a compound provided herein formulated in a compatiblepharmaceutical carrier can also be prepared, placed in an appropriatecontainer, and labeled for treatment of an indicated condition.

EXAMPLES

These examples are provided for illustrative purposes only and not tolimit the scope of the claims provided herein. The starting materialsand reagents used for the synthesis of the compounds described hereinmay be synthesized or can be obtained from commercial sources, such as,but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and FischerScientific.

HPLC methods: Platform (Methods 1-3): Agilent 1100 series HPLC,comprised of pumps, degasser and UV detector, equipped with anauto-sampler. MS detector (APCI) PE Sciex API 150 EX. Platform (Method4): Agilent 1290 series HPLC, comprised of binary pumps, degasser and UVdetector, equipped with an auto-sampler. MS detector AJS-ES.

Method 1: Column—Zorbax C18, size 4.6 mm×7.5 cm; Solvent A: 0.05% TFA inwater, Solvent B: 0.05% TFA in acetonitrile; Flow rate—0.7 mL/min;Gradient: 5% B to 100% B in 9 min, hold at 100% B for 4 min and 100% Bto 5% B in 0.5 min; UV detector—channel 1=220 nm, channel 2=254 nm.

Method 2: Column—Zorbax C18, size 4.6 mm×7.5 cm; Solvent A: 0.05% TFA inwater, Solvent B: 0.05% TFA in acetonitrile; Flow rate—0.7 mL/min;Gradient: 5% B to 100% B in 5 min, hold at 100% B for 2 min and 100% Bto 5% B in 0.5 min; UV detector—channel 1=220 nm, channel 2=254 nm.

Method 3: Column—SunFire™ (Waters) C18, size 2.1 mm×50 mm; Solvent A:0.05% TFA in water, Solvent B: 0.05% TFA in acetonitrile; Flow rate—0.8mL/min; Gradient: 10% B to 90% B in 2.4 min, hold at 90% B for 1.25 minand 90% B to 10% B in 0.25 min, hold at 10% B for 1.5 min.; UVdetector—channel 1=220 nm, channel 2=254 nm.

Method 4: Column—Zorbax Eclipse Plus C18, size 2.1×50 mm; Solvent A:0.10% formic acid in water, Solvent B: 0.00% formic acid inacetonitrile; Flow rate—0.7 mL/min; Gradient: 5% B to 95% B in 5 min andhold at 95% B for 2 min; UV detector—channel 1=254 nm, channel 2=254 nm.

Example 1: Synthesis of(N-methyl{2-[3-(3,4-dichlorophenyl)ureido]-6-methyl-4-pyrimidinyl}amino)methane(2)

Step 1: 1-(4-Chloro-6-methyl-2-pyrimidinyl)-3-(3,4-dichlorophenyl)urea(1)

A mixture of 3,4-dichloro phenyl isocyanate (5 g, 26.6 mmol) and2-amino-4-chloro-6-methylpyrimidine (3.82 g, 26.6 mmol) and 1,4-dioxane(130.0 mL) was heated at reflux for 15 hours. The mixture was cooled andMeOH (50 mL) was added. A white precipitate was collected by filtrationand dried to give compound (1) (6 g, 69%). LC/MS: Rt=3.4 min,m/z=333.3-335.3 [MH⁺].

Step 2:1-(N-Methyl{2-[3-(3,4-dichlorophenyl)ureido]-6-methyl-2-pyrimidinyl}amino)methane(2)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(3,4-dichlorophenyl)urea (1) (83mg, 0.25 mmol), dimethylamine (0.125 mL, 0.25 mmol, 2M solution in THF),diisopropylethylamine (50 μL) and dimethylacetamide (3.0 mL) was heatedto 90-95° C. overnight. The mixture was cooled and MeOH (3.0 mL) wasadded. White precipitates formed which were filtered to afford the titlecompound (2) (45.0 mg, 52%). %). LC/MS: Rt=2.85 min, m/z=340.3-344.2[MH⁺].

Example 2: Synthesis of1-(3,4-dichlorophenyl)-3-(6-methyl-4-piperidino-2-pyrimidinyl)urea (3)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(3,4-dichlorophenyl)urea (1) (83mg, 0.25 mmol), piperidine (106 mg, 1.25 mmol) and dimethylacetamide(3.0 mL) was heated to 90-95° C. overnight. The mixture was cooled andMeOH (3.0 mL) was added. White precipitates formed which were filteredto afford the title compound (3) (63.0 mg, 66%). LC/MS: Rt=2.95 min,m/z=381.9-384.3 [MH⁺].

Example 3: Synthesis of1-(3,4-dichlorophenyl)-3-(6-methyl-4-morpholino-2-pyrimidinyl) urea (4)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(3,4-dichlorophenyl)urea (1) (83mg, 0.25 mmol), morpholine (105 mg, 1.25 mmol) and dimethylacetamide(3.0 mL) was heated to 90-95° C. overnight. The mixture was cooled andMeOH (3.0 mL) was added. A white solid precipitate was collected byfiltration and dried to give the title compound (4) (61 mg, 64%). LC/MS:Rt=3.12 min, m/z=382.3-384.6 [MH⁺].

Example 4: Synthesis of1-(3,4-dichlorophenyl)-3-{6-methyl-4-(4-methyl-piperazin-1-yl-)pyrimidin-2-yl}-urea(5)

A mixture of1-(2-chloro-6-methyl-2-pyrimidinyl)-3-(3,4-dichlorophenyl)urea (1) (83mg, 0.25 mmol), 1-methylpiperazine (27.0 mg, 0.27 mmol),diisopropylethylamine (52 μL) and dimethylacetamide (3.0 mL) was heatedto 90-95° C. overnight. The mixture was cooled and MeOH (3.0 mL) wasadded. White precipitates formed which were filtered to give the titlecompound (5) (55 mg, 56%). LC/MS: Rt=2.82 min, m/z=397.4-399.4 [MH⁺].

Example 5: Synthesis of1-(N-methyl{2-[3-(3,4-dichlorophenyl)ureido]-6-methyl-4-pyrimidinyl}amino)-2-(methylamino)ethane(6)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(3,4-dichlorophenyl)urea (1) (166mg, 0.5 mmol), N,N′-dimethylethane-1,2-diamine (450 mg, 5 mmol), and1,4-dioxane (4.0 mL) was heated to 90-95° C. overnight. The mixture wascooled and MeOH (5.0 mL) was added. White precipitates formed which werefiltered to give the title compound (6) (140 mg, 73%). LC/MS: Rt=2.92min, m/z=384.3-386.4 [MH⁺].

Example 6: Synthesis of3-{2-[3-(3,4-dichlorophenyl)ureido]-6-methyl-pyrimidin-4-yl}-aminopropanol(7)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(3,4-dichlorophenyl)urea (1) (166mg, 0.5 mmol), 3-aminopropanol (73.0 mg, 0.5 mmol), and 1,4-dioxane (4.0mL) was heated to 90-95° C. overnight. The mixture was cooled and MeOH(3.0 mL) was added. White precipitates formed which were filtered togive the title compound (7) (90 mg, 56%). LC/MS: Rt=3.06 min,m/z=372.2-374.5 [MH⁺].

Example 7: Synthesis of1-{2-[3-(3,4-Dichlorophenyl)ureido]-6-methyl-pyrimidin-4-yl}-amino-3-(dimethylamino)propane(8)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(3,4-dichlorophenyl)urea (1) (166mg, 0.5 mmol), N,N′-dimethyl-1,3-propanediamine (510 mg, 5.0 mmol), and1,4-dioxane (4.0 mL) was heated to 90-95° C. overnight. The mixture wascooled and MeOH (3.0 mL) was added. White precipitates formed which werefiltered to give the title compound (8) (64 mg, 33%). LC/MS: Rt=2.96min, m/z=397.2-399.4 [MH⁺].

Example 8: Synthesis of1-(4-((2-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea(9)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(3,4-dichlorophenyl)urea (1) (1.05g, 3.2 mmol) and toluene (4.7 mL) was heated to reflux with stirring. Tothis was added 1,3-propanediamine (0.32 mL, 3.8 mmol), and triethylamine(0.66 mL, 4.7 mmol) and reflux continued. Upon cooling a precipitateformed which was filtered and washed with methanol and diethyl ether togive the title compound (9) (1.01 g, 83%). LC/MS: Method 4: Rt=1.44 min,m/z=368.1-370.1 [MH+].

Example 9: Synthesis of1-{2-[3-(3,4-Dichlorophenyl)ureido]-6-methyl-4-pyrimidinylamino}-2-propanol(10)

1-(4-Chloro-6-methyl-2-pyrimidinyl)-3-(3,4-dichlorophenyl)urea (1) (0.2g, 0.56 mmol) was suspended in 2-propanol (1.1 mL). To this was addedtriethylamine (0.12 mL, 0.89 mmol) and then 1-aminopropan-2-ol (0.06 mL,0.70 mmol), and the mixture was heated to reflux with stirringovernight. Upon cooling a precipitate formed which was filtered andwashed with absolute ethanol to give the title compound (10) (6.4 mg,3%). LC/MS: Method 4: Rt=2.22 min, m/z=370.1-372.1 [MH+]).

The following examples were prepared according to similar proceduresdescribed for Examples 1-9:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 1110

4 0.24 g, 21 2.48 383.2-385.1 12 11

4 27 mg, 18 1.70 356.1-358.1 13 12

4 14 mg, 11 2.18 384.1-386.1 14 13

4 16 mg, 71 1.80 355.1-357.1 15 14

4 0.14 g, 60 1.89 383.1-385.1 16 15

15 mg, 8 1.74 423.2-425.2 17 16

4 0.23 g, 87 2.30 411.2-413.2 18 17

4 0.19 g, 82 2.01 400.1-402.1 19 18

4 17 mg, 9 2.11 383.1-385.1 20 19

4 11 mg, 41 2.62 398.1-400.1 21 20

4 0.20 g, 73 1.96 431.2-433.2 22 21

4 0.20 g, 78 2.85 405.1-407.1

Example 22: Synthesis of(±)-2-[3-(3,4-dichlorophenyl)ureido]-6-methyl-4-(3-piperidylamino)pyrimidinehydrochloride (24)

Step 1: tert-butyl2-(2-(3-(3,4-dichlorophenyl)ureido)-6-methylpyrimidin-4-ylamino)piperidine-1-carboxylate(23)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(3,4-dichlorophenyl)urea (1) (905mg, 2.75 mmol), 1-boc-3-amino-piperidine (901 mg, 4.5 mmol), anddimethylacetamide (9.0 mL) was heated at 85° C. for 5 hours. The mixturewas cooled and added to water. White solids formed that were filteredand washed with 1M HCl and EA and dried (1.03 g, 76%).

Step 2:(±)-2-[3-(3,4-dichlorophenyl)ureido]-6-methyl-4-(3-piperidylamino)pyrimidinehydrochloride (24)

The BOC derivative (9) (741 mg, 1.5 mmol) was suspended into a 9:1mixture of DCM:MeOH (7.5 mL) and HCl (4M in dioxane, 7.5 mL) was added.The reaction mixture was stirred overnight at room temperature.Volatiles were removed in vacuo to yield the title compound (10) as ahydrochloride salt (500 mg). LC/MS: Rt=3.18 min, m/z=395.1 [MH⁺].

Example 23: Synthesis of1-(3,4-dichlorophenyl)-3-(4-methyl-6-((4-(methylamino)butyl)amino)pyrimidin-2-yl)urea(26)

Step 1:(4-{2-[3-(3,4-Dichloro-phenyl)-ureido]-6-methyl-pyrimidin-4-ylamino}-butyl)-methyl-carbamicAcid tert-butyl ester (25)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(3,4-dichlorophenyl)urea (1) (1.4g, 4.3 mmol) and toluene (6.5 mL) was heated to reflux with stirring. Tothis was added N-(4-Aminobutyl)-N-methyl carbamic acid tert-butyl ester(1.0 g, 5.2 mmol), and triethylamine (0.91 mL, 6.4 mmol) and refluxcontinued for 30 minutes. Upon cooling methanol was added and theprecipitate formed was filtered and washed with diethyl ether to givethe title compound (25) (2.0 g, 90%). LC/MS: Rt=3.97 min,m/z=497.2-499.2 [MH+].

Step 2:1-(3,4-dichlorophenyl)-3-(4-methyl-6-((4-(methylamino)butyl)amino)pyrimidin-2-yl)urea

The BOC derivative (25) (2.5 g, 4.7 mmol) was suspended in DCM (15 mL)to which trifluoroacetic acid (9 mL, 118 mmol) was added. The reactionmixture was stirred for 30 minutes at room temperature. This mixture wastreated with 1N NaOH solution (4.7 mL, 4.7 mmol) and the mixture stirredfor 30 minutes. The layers were separated and the organics washed withwater and brine before drying and being concentrated to yield the titleproduct (26) LC/MS: Method 4: Rt=2.31 min, m/z=397.2-399.2 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Examples 22-23:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 2724

4  1.7 g, 91 2.24 409.2-411.2 28 25

4 69 mg, 97 1.77 370.1-372.1 29 26

4 0.37 g, 92 0.35 383.2-385.1

Example 27: Synthesis of(f)-2-[3-(3,4-dichlorophenyl)ureido]-4-(1-ethyl-piperidin-3-yl-amino)-6-methylpyrimidine(30)

To a solution of2-[3-(3,4-dichlorophenyl)ureido]-6-methyl-4-(3-piperidylamino)pyrimidine(24) (215 mg, 0.5 mmol) in DCM (2.5 mL) was added acetaldehyde (141 μL,2.5 mmol) and then sodium cyanoborohydride (63 mg, 1.00 mmol). Thereaction mixture was stirred for 3 hours and then diluted with DCM (10mL) and washed with water, NaHCO₃solution, and water. The organic layerwas dried (Na₂SO₄), filtered and concentrated. The residue was purifiedon silica plate (eluent: DCM:MeOH:NH₄OH: 400:50:2 v/v) to give the titlecompound (30) (50 mg, 24%). LC/MS: Rt=3.05 min, m/z=423.4 [MH⁺].

Example 28: Synthesis of(±)-1-(3,4-dichlorophenyl)-3-[4-(1-ethyl-3-piperidylamino)-6-methyl-2-pyrimidinyl]-2-imidazolidinone(34)

Step 1:3-(4-Chloro-6-methyl-2-pyrimidinyl)-1-(3,4-dichlorophenyl)-2-imidazolidinone(31)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(3,4-dichlorophenyl)urea (1) (150mg, 0.45 mmol), 1,2-dibromoethane (847 mg, 4.53 mmol), K2CO₃ (607 mg,4.53 mmol) in acetone (4.5 mL) was heated to reflux for 3 hours. Thereaction mixture was cooled, poured into water (25.0 mL) and extractedwith EA (2×25 mL). The organic layer was dried (Na₂SO₄), filtered andevaporated to dryness. The residue was purified by chromatography(silica column, eluent 0-40% EA in Hexane, gradient) to yield compound(31) (100 mg, 61.2%). LC/MS: Rt=4.15 min, m/z=357.2 [MH⁺].

Step 2: (±)-tert-butyl3-(2-(3-(3,4-dichlorophenyl)-2-oxoimidazolidin-1-yl)-6-methylpyrimidin-4-ylamino)piperidine-1-carboxylate(32)

A mixture of3-(4-chloro-6-methyl-2-pyrimidinyl)-1-(3,4-dichlorophenyl)-2-imidazolidinone(31) (100 mg, 0.28 mmol), 1-Boc-3-aminopiperidine (901 mg, 4.5 mmol),DIPEA (73 mg, 0.56 mmol) and DMA (3.0 mL) was heated at 85° C. for 5hrs. The reaction was cooled and added to water. White solids formedthat were filtered and washed with 0.1M HCl and EA and dried (100 mg) toyield compound (32).

Step 3:(±)-1-(3,4-Dichlorophenyl)-3-[6-methyl-4-(3-piperidylamino)-2-pyrimidinyl]-2-imidazolidinone(33)

Compound (32) (100 mg, 0.192 mmol) was suspended in DCM (10.0 mL) andTFA (10.0 mL) was added. The mixture was stirred overnight at roomtemperature. Volatiles were removed in vacuo to yield1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(3,4-dichlorophenyl)-2-imidazolidinone(33) (100 mg) as a TFA salt.

Step 4:(±)-1-(3,4-Dichlorophenyl)-3-[4-(1-ethyl-3-piperidylamino)-6-methyl-2-pyrimidinyl]-2-imidazolidinone(34)

3 To a solution of(±)-1-(3,4-dichlorophenyl)-3-[6-methyl-4-(3-piperidylamino)-2-pyrimidinyl]-2-imidazolidinone(33) (100 mg, 0.237 mmol) in DCM (2.5 mL) was added acetaldehyde (52 mg,1.187 mmol) and then sodium cyanoborohydride (29 mg, 0.475 mmol). Thereaction mixture was stirred for 3 hours and then diluted with DCM (10mL). The reaction mixture was washed with water, NaHCO₃solution andwater. The organic layer was dried (Na₂SO₄), filtered and concentratedto yield crude product which was purified on silica plate (eluent,DCM:MeOH:NH₄₀H: 400:50:2) to yield the title compound (34) (15 mg, 14%).LC/MS: Rt=0.05 min, m/z=450.6 [MH⁺].

Example 29: Synthesis of3-(3,4-dichlorophenyl)-1-[4-(3-hydroxypropylamino)-6-methyl-2-pyrimidinyl]-2-imidazolidinone(35)

3-(4-Chloro-6-methyl-2-pyrimidinyl)-1-(3,4-dichlorophenyl)-2-imidazolidinone(31) (50 mg, 0.14 mmol), 3-aminopropanol (16 mg, 0.21 mmol), DIPEA (271mg, 2.1 mmol) were taken into DMA (3.0 mL) and heated at 80° C. for 12hours. Then the reaction mixture was cooled and water was added. Thedesired compound precipitated which was crystallized using MeOH and DCMmixture. The resulting crystals were filtered and dried to give thetitle compound (35) (25 mg, 45%). LC/MS: Rt=4.24 min, m/z=397.3 [MH⁺].

Example 30: Synthesis of3-(3,4-dichlorophenyl)-1-{4-[3-(dimethylamino)propylamino]-6-methyl-2-pyrimidinyl}-2-imidazolidinone(36)

3-(4-Chloro-6-methyl-2-pyrimidinyl)-1-(3,4-dichlorophenyl)-2-imidazolidinone(31) (50 mg, 0.14 mmol), 3-(dimethylamino)propylamine (21 mg, 0.21mmol), DIPEA (271 mg, 2.1 mmol) were taken into DMA (3.0 mL) and heatedat 80° C. for 12 hours. The reaction mixture was cooled and water added.The desired compound precipitated which was crystallized using MeOH andDCM mixture. The resulting crystals were filtered and dried to give thetitle compound (36) (25 mg, 45%). LC/MS: Rt=4.16 min, m/z=424.3 [MH⁺].

Example 31: Synthesis of1-(3,4-dichlorophenyl)-3-[6-methyl-4-(4-pyridyloxy)-2-pyrimidinyl]-urea(37)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(3,4-dichlorophenyl)urea (1) (50mg, 0.15 mmol), K2CO₃ (42.0 mg, 0.30 mmol) and 4-hydroxypyridine (21.0mg, 0.225 mmol) in 1,4-dioxane was stirred at 100° C. for 4 hours. Thereaction mixture was cooled, diluted with water and extracted with EA(2×10 mL). The organic layers were dried (Na₂SO₄), filtered andconcentrated to yield title compound (37) (28.0 mg, 48%) as a solid.LC/MS: Rt=3.09 min, m/z=390.4 [MH⁺].

Example 32: Synthesis of1-(3,4-dichlorophenyl)-3-[6-methyl-4-(3-pyridyloxy)-2-pyrimidinyl]-urea(38)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(3,4-dichlorophenyl)urea (1) (50mg, 0.15 mmol), K2CO₃ (42 mg, 0.30 mmol) and 3-hydroxypyridine (21 mg,0.225 mmol) in 1,4-dioxane was stirred at 100° C. for 4 hours. Thisreaction mixture was cooled, diluted with water and extracted with EA(2×10 mL). The organic layer was dried (Na₂SO₄), filtered andconcentrated to yield title compound (38) (29 mg, 50%) as a solid.LC/MS: Rt=3.26 min, m/z=390.4 [MH⁺].

Example 33: Synthesis of2-[3-(3,4-dichlorophenyl)ureido]-6-methyl-4-(4-pyridylamino)-pyrimidine(39)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(3,4-dichlorophenyl)urea (1) (50mg, 0.15 mmol), 4-aminopyridine (21.0 mg, 0.225 mmol),diisopropylethylamine (52 μL, 0.30 mmol) was heated in DMA (1.5 mL) for4 hours. The reaction mixture was cooled, diluted with water andextracted with EA (2×10 mL). The organic layer was dried (Na₂SO₄),filtered and concentrated to yield the title compound (39) (30 mg, 52%)as a solid. LC/MS: Rt=0.04 min, m/z=389.3 [MH⁺].

Example 34: Synthesis of3-{2-[3-(p-Chlorophenyl)ureido]-6-methyl-4-pyrimidinylamino}-propanol(41)

Step 1: 1-(4-Chloro-6-methyl-2-pyrimidinyl)-3-(p-chlorophenyl)urea (40)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (72 mg, 0.5 mmol) and4-chloro-phenyl isocyanate (115 mg, 0.75 mmol) in 1,4-dioxane (1 mL) washeated for 3 hours at 100° C. The mixture was concentrated in vacuo andthe residue was triturated with MeOH, filtered and dried to yieldcompound (40) (72 mg, 49%) as a white solid.

Step 2:3-{2-[3-(p-Chlorophenyl)ureido]-6-methyl-4-pyrimidinylamino}-propanol(41)

A mixture of 1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(p-chlorophenyl)urea(40) (36 mg, 0.12 mmol) and 3-amino-1-propanol (46 mg, 0.61 mmol) in DMA(1 mL) was heated for 3 hours at 100° C. The mixture was cooled. A whiteprecipitate was filtered and air-dried to yield the title compound (41)(20 mg, 49%). LC/MS: Rt=0.30 min, m/z=336.6 [MH⁺].

Example 35: Synthesis of3-{2-[3-(m-chlorophenyl)ureido]-6-methyl-4-pyrimidinylamino}-propanol(43)

Step 1: 1-(4-Chloro-6-methyl-2-pyrimidinyl)-3-(m-chlorophenyl)urea (42)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (72 mg, 0.5 mmol) and3-chloro-phenyl isocyanate (115 mg, 0.75 mmol) in 1,4-dioxane (1 mL) washeated for 3 hours at 100° C. The mixture was concentrated in vacuo andthe residue was triturated with MeOH, filtered and dried to yieldcompound (42) (115 mg, 88%) as a white solid.

Step 2:3-{2-[3-(m-Chlorophenyl)ureido]-6-methyl-4-pyrimidinylamino}-propanol(43)

A mixture of 1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(m-chlorophenyl)urea(38) (58 mg, 0.22 mmol) and 3-amino-1-propanol (50 mg, 0.66 mmol) in DMA(1 mL) was heated for 3 hours at 100° C. The mixture was cooled. A whiteprecipitate was filtered and air-dried to yield the title compound (43)(54 mg, 82%). LC/MS: Rt=0.11 min, m/z=336.6 [MH⁺].

Example 36: Synthesis of1-{2-[3-(4-chloro-phenyl)ureido]-6-methyl-4-pyrimidin-ylamino}-3-(dimethylamino)propane(44)

A mixture of 3-(4-chlorophenyl)-1-(4-chloro-6-methyl-2-pyrimidinyl)urea(40) (36.0 mg, 0.121 mmol) and 3-(dimethylamino)-1-propylamine (37.1 mg,0.364 mmol) in DMA (1.0 mL) was heated for 3 hours at 100° C. Themixture was cooled. A white precipitate was filtered and air-dried toyield the title compound (44) (26 mg, 59%). LC/MS: Rt=0.53 min,m/z=363.4 [MH⁺].

Example 37: Synthesis of1-{2-[3-(3-Chloro-phenyl)ureido]-6-methyl-4-pyrimidin-ylamino}-3-(dimethyl-amino)propane(45)

A mixture of 3-(3-chloro-phenyl)-1-(4-chloro-6-methyl-2-pyrimidinyl)urea(42) (58 mg, 0.22 mmol) and 3-(dimethylamino)-1-propylamine (135 mg,0.66 mmol) in DMA (1.0 mL) was heated for 3 hours at 100° C. The mixturewas cooled. A white precipitate was filtered and air-dried to yield thetitle compound (45) (22 mg, 31%). LC/MS: Rt=3.84 min, m/z=363.6 [MH⁺].

Example 38: Synthesis of1-(2-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}-6-methyl-4-pyrimidinylamino)-3-(dimethylamino)propane(47)

Step 1:3-(4-Chloro-6-methyl-2-pyrimidinyl)-1-[4-chloro-3-(trifluoromethyl)phenyl]urea (46)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (72.0 mg, 0.5 mmol) and4-chloro-(3-trifluoromethyl)phenyl isocyanate (166.2 mg, 0.75 mmol) in1,4-dioxane (1.0 mL) was heated for 3 hours at 100° C. The reactionmixture was cooled and precipitate product was filtered, washed with1,4-dioxane and dried to yield compound (46) (129 mg, 70%) as a whitesolid.

Step 2:1-(2-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}-6-methyl-4-pyrimidinylamino)-3-(dimethylamino)propane(47)

A mixture of3-(4-chloro-6-methyl-2-pyrimidinyl)-1-[4-chloro-3-(trifluoromethyl)phenyl]urea (46) (129 mg, 0.35 mmol) and 3-(dimethylamino)-1-propylamine(107 mg, 1.05 mmol) in DMA (1.0 mL) was heated for 3 hrs at 100° C. Themixture was cooled and a white precipitate was filtered, washed withwater and air dried to yield the title compound (47) (128 mg, 85%).LC/MS: Rt=0.17 min, m/z=431.3 [MH⁺].

Example 39: Synthesis of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((2-(dimethylamino)ethyl)amino)-6-methylpyrimidin-2-yl)urea(48)

A suspension of3-(4-chloro-6-methyl-2-pyrimidinyl)-1-[4-chloro-3-(trifluoromethyl)phenyl]urea (46) (100 mg, 0.26 mmol), N,N-dimethylethylene-diamine (28mg, 0.31 mmol) and trimethylamine (39 mg, 0.39 mmol) in 2-propanol (1mL) was heated to reflux at 90° C. After 30 minutes the mixture wascooled to ambient temperature and diluted with MeOH. The title compound(48) was filtered as a white solid (85 mg, 78%). LC/MS: Method 4:Rt=1.96 min, m/z=418.2-420.2 [MH+].

The following examples were prepared according to similar proceduresdescribed for Examples 38-39:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 4940

4 88 mg, 82 2.23 390.1-392.1 50 41

4 82 mg, 72 2.25 419.2-421.2 51 42

4 99 mg, 83 2.23 435.2-437.2 52 43

4 92 mg, 80 2.12 421.2-423.2 53 44

4 23 mg, 19 2.66 441.1-443.1 54 45

4 83 mg, 75 2.16 405.2-407.2 55 46

4 96 mg, 90 1.79 389.2-391.2 56 47

4 82 mg, 67 1.80 445.2-447.2 57 48

4 108 mg, 87  2.02 451.2-453.2 58 49

4 91 mg, 76 1.78 441.2-443.2 59 50

4 43 mg, 35 1.71 454.2-456.2 60 51

4 52 mg, 46 2.01 418.2-420.1 61 52

4 10 mg, 17 2.82 439.2-441.2

Example 53:1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)urea(63)

Step 1:tert-butyl(2-((2-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)(methyl)carbamate(62)

A mixture of3-(4-chloro-6-methyl-2-pyrimidinyl)-1-[4-chloro-3-(trifluoromethyl)phenyl]urea (46) (100 mg, 0.26 mmol), N-(2-Aminoethyl)-N-methyl carbamicacid tert-butyl ester (56 mg, 0.31 mmol), and triethylamine (40 mg, 0.39mmol) was heated to reflux with stirring in 2-propanol (1 mL) for 30minutes. Upon cooling methanol was added and the precipitate formed wasfiltered to give the title compound (62) (97 mg, 70%). LC/MS: Rt=3.11min, m/z=504.2-506.2 [MH+].

Step 2:1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)urea(63)

The BOC derivative (62) (97 mg, 0.18 mmol) was suspended in DCM (1.8 mL)to which trifluoroacetic acid (0.15 mL, 1.8 mmol) was added. Thereaction mixture was stirred for 3 hours before addition of moretrifluoroacetic acid (0.15 mL). This mixture was warmed to 45° C. andstirred overnight. The solvent was removed under reduced pressure toobtain a yellow gel which was mixed with saturated NaHCO₃solution. Noprecipitation was observed, thus the solvent was removed under reducedpressure and the resulting residue was purified by flash chromatography(gradient elution, 0-20% 3M NH₃ in MeOH over CH₂Cl₂) to obtain thedesired compound as a white solid (63) (51 mg, 66%). LC/MS: Method 4:Rt=1.80 min, m/z=404.2-406.2 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Example 53:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 6454

4 66 mg, 86 1.72 417.2-419.2 65 55

4 37 mg, 48 1.73 431.2-433.2 66 56

4 100 mg, 88  1.78 443.2-445.1 67 57

4 62 mg, 85 1.78 415.1-417.1

Example 58: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-phenylurea(69)

Step 1: 1-(4-Chloro-6-methyl-2-pyrimidinyl)-3-phenylurea (68)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (72.0 mg, 0.5 mmol) andphenyl isocyanate (90.0 mg, 0.75 mmol) in 1,4-dioxane (1.00 mL) washeated for 3 hours at 100° C. Volatiles were removed under vacuum andthe residue was triturated with MeOH, filtered and dried to yieldcompound (68) (78.0 mg, 58%) as a white solid.

Step 2:1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-phenylurea(69)

A mixture of 1-(4-chloro-6-methyl-2-pyrimidinyl)-3-phenylurea (68) (37.0mg, 0.143 mmol), and 3-(dimethylamino)-1-propylamine (107 mg, 1.05 mmol)in DMA (1.0 mL) was heated for 3 hours at 100° C. The reaction mixturewas cooled and treated with water. A white precipitate was filtered andair dried to yield the title compound (69) (41 mg, 87%). LC/MS: Rt=4.41min, m/z=329.4 [MH⁺].

Example 59: Synthesis of1-(4-((3-hydroxypropyl)amino)-6-methylpyrimidin-2-yl)-3-phenylurea (70)

A mixture of 1-(4-chloro-6-methyl-2-pyrimidinyl)-3-phenylurea (68) (37mg, 0.143 mmol) and 3-amino-1-propanol (54 mg, 0.715 mmol) in DMA (1.0mL) was heated for 3 hours at 100° C. The mixture was cooled and treatedwith water. A white precipitate was filtered and air-dried to yield thetitle compound (70) (23 mg, 53%). LC/MS: Rt=0.05 min m/z=423.1 [MH⁺].

Example 60: Synthesis of1-(4-((2-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea(71)

A mixture of 1-(4-chloro-6-methyl-2-pyrimidinyl)-3-phenylurea (68) (0.3g, 1.1 mmol) and toluene (1.5 mL) was treated with triethylamine (0.21mL, 1.5 mmol) and 2-aminoethanol (0.08 mL, 1.2 mmol), and then heated toreflux with stirring. Upon cooling a precipitate formed which wasfiltered and washed with methanol and diethyl ether to give the titlecompound (71) (0.26 g, 85%). LC/MS: Method 4: Rt=1.75 min, m/z=288.1[MH+].

Example 61: Synthesis of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-phenylurea (72)

1-(4-chloro-6-methyl-2-pyrimidinyl)-3-phenylurea (68) (0.2 g, 0.76 mmol)was suspended in 2-propanol (1.5 mL). To this was added triethylamine(0.15 mL, 1.1 mmol) and then ethane-1,2-diamine (0.06 mL, 0.91 mmol),and the mixture was heated to reflux with stirring overnight. Uponcooling a precipitate formed which was filtered to give the titlecompound (72) (0.21 g, 91%). LC/MS: Method 4: Rt=0.86 min, m/z=287.2[MH+].

The following examples were prepared according to similar proceduresdescribed for Examples 58-61:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 7362

4 110 mg, 32  1.96 316.2 74 63

4 61 mg, 44 0.36 315.2 75 64

4 61 mg, 22 0.41 301.2 76 65

4 80 mg, 32 0.36 343.3 77 66

4 23 mg, 15 0.34 302.2 78 67

4 72 mg, 60 1.29 318.2 79 68

4 22 mg, 17 1.64 338.2 80 69

4 28 mg, 20 1.97 337.2

Example 70:1-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)-3-phenylurea(82)

Step 1: tert-butylmethyl(2-((6-methyl-2-(3-phenylureido)pyrimidin-4-yl)amino)ethyl)carbamate(81)

A mixture of 1-(4-chloro-6-methyl-2-pyrimidinyl)-3-phenylurea (68) (200mg, 0.78 mmol) and toluene (1.2 mL) was treated withN-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (0.17 mL, 0.94mmol), and triethylamine (0.16 mL, 1.2 mmol) and this was heated toreflux with stirring. Upon cooling methanol was added and theprecipitate formed was filtered and washed with diethyl ether to givethe title compound (81) (212 mg, 64%). LC/MS: Method 4: Rt=0.36 min,m/z=401.3 [MH+].

Step 2:1-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)-3-phenylurea

The BOC derivative (81) (0.2 g, 0.5 mmol) was suspended in DCM (5 mL) towhich trifluoroacetic acid (0.98 mL, 12 mmol) was added. The reactionmixture was stirred for 15 minutes at room temperature beforeevaporation of the solvent. This mixture was treated with DCM and 1NNaOH solution (0.5 mL, 0.5 mmol) and the mixture stirred for 10-30minutes. The suspension was filtered to yield the title product (82) asa white solid (145 mg, 86%) LC/MS: Method 4: Rt=0.36 min, m/z=301.2[MH+].

Example 71:1-(4-methyl-6-((3-(methylamino)propyl)amino)pyrimidin-2-yl)-3-phenylurea(83)

Example 71 was prepared by a procedure similar to example 70 from1-(4-chloro-6-methyl-2-pyrimidinyl)-3-phenylurea (68) andN-(3-aminopropyl)-N-methyl carbamic acid tert-butyl ester. (28 mg, 11%)LC/MS: Method 4: Rt=0.38 min, m/z=315.2 [MH⁺].

Example 72: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(85)

Step 1:1-(4-Chloro-6-methyl-2-pyrimidinyl)-3-(p-trifluoromethoxyphenyl)urea(84)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (72.0 mg, 0.5 mmol) and4-(trifluoromethoxy)phenyl isocyanate (152.0 mg, 0.75 mmol) in dioxane(1.00 mL) was heated for 3 hours at 100° C. Volatiles were removed undervacuum and the residue was triturated with MeOH, filtered and dried toyield compound (84) (120.0 mg, 69%) as a white solid.

Step 2:1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(85)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(p-trifluoromethoxyphenyl)urea(25) (60 mg, 0.173 mmol), and 3-(dimethylamino)-1-propylamine (54 mg,1.05 mmol) in DMA (1.0 mL) was heated for 3 hrs at 100° C. The reactionmixture was cooled and treated with water. A white precipitate wasfiltered and air dried to yield the title compound (26) (41 mg, 57%).LC/MS: Rt=0.33 min, m/z=413.3 [MH⁺].

Example 73: Synthesis of1-(4-((3-hydroxypropyl)amino)-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(86)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(p-trifluoromethoxyphenyl)urea(84) (60 mg, 0.17 mmol) and 3-amino-1-propanol (65 mg, 0.86 mmol) in DMA(1.0 mL) was heated for 3 hours at 100° C. The mixture was cooled. Awhite precipitate was filtered and air-dried to yield the title compound(86) (35 mg, 52%). LC/MS: Rt=0.13 min, m/z=386.4 [MH⁺].

Example 74: Synthesis of1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(87)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(p-trifluoromethoxyphenyl)urea(84) (75 mg, 0.21 mmol) was suspended in 2-propanol (0.4 mL). To thismixture was added triethylamine (0.04 mL, 0.32 mmol) and thenethane-1,2-diamine (0.02 mL, 0.25 mmol), and the mixture was heated toreflux with stirring for several hours. Upon cooling and dilution withmethanol (3 mL), a precipitate formed which was filtered to give thetitle compound (87) (54 mg, 68%). LC/MS: Method 4: Rt=1.50 min,m/z=386.4 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Examples 72-74:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 8875

4 33 mg, 39 1.45 400.2 89 76

4 45 mg, 54 1.59 386.2 90 77

4 54 mg, 71 2.27 357.2 91 78

4 64 mg, 80 2.45 371.2 92 79

4 66 mg, 74 2.34 415.2 93 80

4 55 mg, 64 1.94 399.2 94 81

4 18 mg, 20 2.32 422.2 95 82

4 52 mg, 62 2.01 386.2 96 83

4 38 mg, 44 1.90 403.2

Example 84: Synthesis of1-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(98)

Step 1: tert-Butylmethyl(2-((6-methyl-2-(3-(4-(trifluoromethoxy)phenyl)ureido)pyrimidin-4-yl)amino)ethyl)carbamate(97)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(p-trifluoromethoxyphenyl)urea(84) (75 mg, 0.22 mmol) and 2-propanol (0.43 mL) was treated withN-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (0.05 mL, 0.25mmol), and triethylamine (0.05 mL, 0.32 mmol) and this was heated toreflux with stirring for 5 hours. Upon cooling methanol (3 mL) was addedand the precipitate formed was filtered to give the title compound (97)(68 mg, 65%). LC/MS: Method 4: Rt=2.74 min, m/z=485.3 [MH+].

Step 2:1-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea

The BOC derivative (97) (75 mg, 0.16 mmol) was suspended in DCM (0.12mL) to which trifluoroacetic acid (0.12 mL, 1.6 mmol) was added. After 5hours at room temperature the mixture was treated with saturated sodiumbicarbonate solution until a pH of 8 was reached. The suspension soformed was filtered to yield the title product (98) as a white solid (59mg, 97%) LC/MS: Method 4: Rt=1.50 min, m/z=385.2 [MH⁺].

Example 85:1-[4-Methyl-6-(3-methylamino-propylamino)-pyrimidin-2-yl]-3-(4-trifluoromethoxy-phenyl)-urea(99)

Example 85 was prepared by a procedure similar to example 84 from1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(p-trifluoromethoxyphenyl)urea(84) and N-(3-aminopropyl)-N-methyl carbamic acid tert-butyl esterexcept the intermediate carbamate was first purified by preparative TLCeluting with 10% 1M NH₄OH in MeOH/90% DCM (36 mg, 41%) LC/MS: Method 4:Rt=1.57 min, m/z=400.2 [MH⁺].

Example 86: Synthesis of3-(dimethylamino)-1-(2-{3-[4-fluoro-3-(trifluoromethyl)phenyl]ureido}-6-methyl-4-pyrimidinylamino)propane(101)

Step 1:1-(4-Chloro-6-methy-2-pyrimidinyl)-3-[4-fluoro-3-(trifluoromethyl)-phenyl]urea(100)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (72 mg, 0.5 mmol) and4-fluoro-3-(trifluoromethyl)phenyl isocyanate (154 mg, 0.75 mmol) in1,4-dioxane (1 mL) was heated for 3 hours at 100° C. The reactionmixture was cooled and precipitated product was filtered, washed with1,4-dioxane and dried to yield compound (100) (144 mg, 83%) as a whitesolid.

Step 2:3-(Dimethylamino)-1-(2-{3-[4-fluoro-3-(trifluoromethyl)phenyl]ureido}-6-methyl-4-pyrimidinylamino)propane(101)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-[4-fluoro-3-(trifluoromethyl)-phenyl]urea(100) (60 mg, 0.172 mmol) and 3-(dimethylamino)-1-propylamine (53 mg,0.516 mmol) in DMA (1 mL) was heated for 3 hours at 100° C. The mixturewas cooled and treated with water. A white precipitate was filtered andair-dried to yield the title compound (101) (50 mg, 70%). LC/MS: Rt=0.32min, m/z=415.5 [MH⁺].

Example 87: Synthesis of1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((3-hydroxypropyl)amino)-6-methylpyrimidin-2-yl)urea(102)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-[4-fluoro-3-(trifluoromethyl)-phenyl]urea(100) (84 mg, 0.24 mmol) and 3-amino-1-propanol (91 mg, 1.2 mmol) in DMA(1.0 mL) was heated for 3 hours at 100° C. The mixture was cooled andtreated with water. A white precipitate was filtered and air-dried toyield the title compound (102) (66 mg, 71%). LC/MS: Rt=0.21 min,m/z=388.5 [MH⁺].

Example 88: Synthesis of1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((2-(dimethylamino)ethyl)amino)-6-methylpyrimidin-2-yl)urea(103)

A suspension of3-(4-fluoro-6-methyl-2-pyrimidinyl)-1-[4-chloro-3-(trifluoromethyl)phenyl]urea (100) (100 mg, 0.26 mmol), N,N-dimethylethylene-diamine(0.04 mL, 0.33 mmol) and trimethylamine (0.06 mL, 0.41 mmol) in2-propanol (1 mL) was heated to reflux at 90° C. After 30 minutes themixture was cooled to ambient temperature and diluted with MeOH. Thetitle compound (103) was filtered as a white solid. (65 mg, 57%). LC/MS:Method 4: Rt=1.57 min, m/z=401.2 [MH+].

The following examples were prepared according to similar proceduresdescribed for Examples 86-88:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 10489

4 37 mg, 30 1.68 429.3 105 90

4 56 mg, 52 1.86 374.2 106 91

4 80 mg, 70 2.07 403.2 107 92

4 72 mg, 60 1.93 418.2 108 93

4 35 mg, 61 1.90 404.2 109 94

4 24 mg, 39 2.40 426.2 110 95

4 17 mg, 32 1.57 373.2 111 96

4 30 mg, 54 1.57 387.2 112 97

4 41 mg, 71 1.61 401.2 113 98

4 51 mg, 86 1.73 415.2 114 99

4 27 mg, 44 1.52 424.2 115 100

4 41 mg, 65 1.61 438.2 116 101

4 40 mg, 70 1.90 402.2 117 102

4 40 mg, 78 2.29 359.2 118 103

4 23 mg, 38 2.54 423.2

Example 104: Synthesis of1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)urea(120)

Step 1: tert-Butyl(2-((2-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)(methyl)carbamate(119)

A mixture of1-(4-chloro-6-methyl-2-pyrimidinyl)-3-[4-fluoro-3-(trifluoromethyl)-phenyl]urea(100) (100 mg, 0.27 mmol) and 2-propanol (1 mL) was treated withN-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (0.06 mL, 0.32mmol), and triethylamine (0.06 mL, 0.41 mmol) and this was heated toreflux with stirring for 30 minutes. Upon cooling ethanol was added andthe precipitate formed was filtered to give the title compound (119)(116 mg, 83%). LC/MS: Method 4: Rt=2.77 min, m/z=487.3 [MH+].

Step 2:1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)urea

The BOC derivative (119) (116 mg, 0.12 mmol) was suspended in DCM (1.2mL) to which trifluoroacetic acid (0.18 mL, 2.26 mmol) was added. After3 hours at room temperature, the mixture was warmed to 45° C. andstirred overnight. After cooling the solvent was evaporated and theresidue treated with saturated sodium bicarbonate solution. The solventwas evaporated and the resulting residue was purified by flashchromatography (gradient elution, 0-25% 3M NH₃ in MeOH over CH₂Cl₂) toobtain the desired compound as a white solid (120) (77 mg, 84%). LC/MS:Method 4: Rt=1.38 min, m/z=387.2 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Example 104:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 121105

4 69 mg, 60 1.57 401.2 122 106

4 89 mg, 73 1.51 428.2 123 107

4 75 mg, 66 1.49 400.2

Example 108: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(4-methoxy)phenyl)urea(125)

Step 1: 1-(4-Chloro-6-methyl-2-pyrimidinyl)-3-(4-methoxyphenyl)urea(124)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (2.6 g, 17.6 mmol) and4-methoxyphenyl isocyanate (2.7 g, 17.6 mmol) in toluene (31 mL) wasrefluxed under a stream of N₂ overnight. On cooling the suspension wasfiltered, washed with EtOH and Et₂O and dried to yield compound (124)(5.1 g, 65%) as a white solid. LC/MS: Method 4: Rt=2.95 min, m/z=293.1[MH⁺].

Step 2:1-(4-((3-(Dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(4-(methoxy)phenyl)urea(125)

A mixture of 1-(4-chloro-6-methyl-2-pyrimidinyl)-3-(p-methoxyphenyl)urea(124) (100 mg, 0.32 mmol), and 3-(dimethylamino)-1-propylamine (0.05 mL,0.39 mmol) and triethylamine (0.07 mL, 0.49 mmol) in 2-propanol (0.5 mL)was heated for 2 hrs at 80° C. The reaction mixture was cooled and thewhite precipitate was filtered to yield the title compound (125) (53 mg,43%). LC/MS: Method 4: Rt=1.02 min, m/z=359.3 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Example 108:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 126109

4 206 mg, 77 1.61 346.2 127 110

4  83 mg, 31 1.1 317.2 128 111

4 100 mg, 40 1.97 316.2 129 112

4 222 mg, 85 2.22 330.2 130 113

4 189 mg, 78 1.48 318.2 131 114

4 229 mg, 75 1.05 331.2 132 115

4 120 mg, 42 1.52 362.2 133 116

4  86 mg, 69 1.51 333.2 134 117

4 100 mg, 70 1.28 379.2 135 118

4  80 mg, 61 1.36 348.2 136 119

4  5 mg, 4 1.94 367.2 137 120

4  82 mg, 66 1.07 345.3 138 121

4  28 mg, 21 1.12 345.2 139 122

4  9 mg, 8 1.76 302.2

Example 123: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(3-methoxy)phenyl)urea(141)

Step 1:1-(4-Chloro-6-methyl-2-pyrimidinyl)-3-(3-methoxyphenyl)urea (140)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (3 g, 20.9 mmol) and3-methoxyphenyl isocyanate (3.4 g, 23.0 mmol) in N, N-dimethylacetamide(28 mL) was heated for 80 minutes at 100° C. Upon cooling the mixturewas diluted with MeOH (75 mL), filtered and dried to yield compound(140) (3.1 g, 51%) as a white solid.

Step 2:1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(3-(methoxy)phenyl)urea(141)

1-(4-Chloro-6-methyl-2-pyrimidinyl)-3-(3-methoxyphenyl)urea (140) (75mg, 0.26 mmol), and 3-(dimethylamino)-1-propylamine (0.04 mL, 0.31 mmol)and triethylamine (0.05 mL, 0.38 mmol) in 2-propanol (0.5 mL) was heatedfor 23 hrs at 80° C. The reaction mixture was cooled and diluted with2-propanol (3 mL). A white precipitate was filtered and washed withethanol to yield the title compound (141) (18 mg, 19%). LC/MS: Method 4:Rt=0.32 min, m/z=359.3 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Example 123:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 142124

4 10 mg, 11 0.34 345.3 143 125

4  9 mg, 10 1.08 331.2 144 126

4 16 mg, 19 0.34 317.2 145 127

4 22 mg, 25 0.34 345.3 146 128

4 21 mg, 29 0.33 346.2 147 129

4 5 mg, 6 1.60 332.2 148 130

4 15 mg, 15 1.21 373.3 149 131

4 29 mg, 29 1.23 382.2 150 132

4 24 mg, 26 1.24 368.2 151 133

4 17 mg, 19 1.45 348.2

Example 134: Synthesis of1-(3-methoxyphenyl)-3-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)urea(153)

Step 1: tert-butyl(2-((2-(3-(3-methoxyphenyl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)(methyl)carbamate(152)

A mixture of 1-(4-chloro-6-methylpyrimidin-2-yl)-3-(3-methoxyphenyl)urea(140) (75 mg, 0.26 mmol) and 2-propanol (1 mL) was treated withN-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (0.06 mL, 0.31mmol), and triethylamine (0.05 mL, 0.38 mmol) and this was heated toreflux with stirring for 30 minutes. Upon cooling methanol (5 mL) wasadded and the precipitate formed was filtered to give the title compound(152) (69 mg, 62%).

Step 2:1-(3-methoxyphenyl)-3-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)urea

The BOC derivative (152) (69 mg, 0.16 mmol) was suspended in DCM (0.11mL) to which trifluoroacetic acid (0.12 mL, 1.5 mmol) was added. After 2hours at room temperature the mixture was treated with saturated sodiumbicarbonate solution. The title product was filtered as a white solid(153) (19 mg, 37%). LC/MS: Method 4: Rt=0.95 min, m/z=331.2 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Example 134:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 154135

4 23 mg, 25 1.23 359.3 155 136

4 19 mg, 20 1.33 371.3

Example 137: Synthesis of1-(3-chloro-4-fluorophenyl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)urea(157)

Step 1:1-(3-chloro-4-fluorophenyl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea(156)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (5 g, 34 mmol) and4-methoxyphenyl isocyanate (5.9 g, 34 mmol) in toluene (60 mL) wasrefluxed under a stream of N₂ overnight. On cooling, the suspension wasfiltered, washed with MeOH and Et₂O and dried to yield compound (156)(5.1 g, 48%) as a white solid. LC/MS: Method 4: Rt=0.23 min,m/z=315.0-317.1 [MH⁺].

Step 2:1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(4-(methoxy)phenyl)urea(157)

A mixture of1-(3-chloro-4-fluorophenyl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea(156) (100 mg, 0.30 mmol), and 3-(dimethylamino)-1-propylamine (0.04 mL,0.36 mmol) and triethylamine (0.06 mL, 0.45 mmol) in 2-propanol (0.5 mL)was heated for 2 hrs at 80° C. The reaction mixture was cooled and thewhite precipitate was filtered to yield the title compound (157) (83 mg,69%). LC/MS: Method 4: Rt=1.38 min, m/z=382.2-384.2 [MH⁺].

Example 138: Synthesis of1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(3-chloro-4-fluorophenyl)urea(158)

A mixture of1-(3-chloro-4-fluorophenyl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea(156) 1480 mg, mmol), and 1,3-diaminopropane (0.05 mL, 0.54 mmol) andtriethylamine (0.06 mL, 0.45 mmol) in toluene (0.7 mL) was heated atreflux for 1.5 hrs. The reaction mixture was cooled and the whiteprecipitate was filtered, then washed with MeOH and Et₂O to yield thetitle compound (158) (83 mg, 69%). LC/MS: Method 4: Rt=0.39 min,m/z=353.1-356.2 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Example 137-138:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 159139

4 150 mg, 76 0.38 367.2-370.2 160 140

4 140 mg, 76 0.36 367.2-369.2 161 141

4  80 mg, 59 0.34 340.1-342.1 162 142

4 102 mg, 67 1.52 339.1-341.1 163 143

4 109 mg, 71 2.02 368.2-370.2 164 144

4 155 mg, 67 1.99 354.2-356.1 165 145

4 201 mg, 86 0.32 338.2-340.2 166 146

4  37 mg, 15 0.35 384.2-386.2 167 147

4  56 mg, 22 2.33 382.2-384.2

Example 148: Synthesis of1-(3-chloro-4-fluorophenyl)-3-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)urea(169)

Step 1: tert-Butyl(2-((2-(3-(3-chloro-4-fluorophenyl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)(methyl)carbamate(168)

A mixture of1-(3-chloro-4-fluorophenyl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea(156) (206 mg, 0.62 mmol) and toluene (2.3 mL) was treated withN-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (0.14 mL, 0.74mmol), and triethylamine (0.13 mL, 0.93 mmol) and this was heated toreflux with stirring for 1 hour. Upon cooling the precipitate formed wasfiltered and washed with MeOH and Et₂O to give the title compound (168)(189 mg, 64%). LC/MS: Method 4: Rt=0.33 min, m/z=453.2-455.2 [MH⁺].

Step 2:1-(3-Chloro-4-fluorophenyl)-3-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)urea(169)

The BOC derivative (168) (189 mg, 0.40 mmol) was suspended in DCM (5 mL)to which trifluoroacetic acid (0.77 mL, 9.9 mmol) was added. After 15minutes at room temperature the solvent was evaporated and the residuetreated with DCM and 1N sodium hydroxide solution. The title product wasfiltered and washed with water to yield a white solid (169) afterdrying. (117 mg, 79%) LC/MS: Method 4: Rt=0.36 min, m/z=353.2-355.2[MH⁺].

Example 149: Synthesis of1-(3-chloro-4-fluorophenyl)-3-(4-methyl-6-((3-(methylamino)propyl)amino)pyrimidin-2-yl)urea(170)

Example 149 was prepared in a similar manner to example 148 from1-(3-chloro-4-fluorophenyl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea(156) and N-(3-aminopropyl)-N-methyl carbamic acid tert-butyl ester (165mg, 93%). LC/MS: Method 4: Rt=0.38 min, m/z=367.2-369.2 [MH+].

Example 150: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(3-(trifluoromethoxy)phenyl)urea(172)

Step 1:1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(3-(trifluoromethoxy)phenyl)urea(171)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (179 mg, 1.2 mmol) and3-trifluoromethoxyphenyl isocyanate (278 mg, 1.4 mmol) in toluene (1.7mL) was refluxed for 7 hours. On cooling, MeOH (5 mL) was added and thesuspension was filtered, washed with Et₂O and dried to yield compound(171) (66 mg, 15%) as a white solid.

Step 2:1-(4-((3-(Dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(3-(trifluoromethoxy)phenyl)urea(172)

A mixture of1-(4-chloro-6-methylpyrimidin-2-yl)-3-(3-(trifluoromethoxy)phenyl)urea(171) (66 mg, 0.19 mmol), and 3-(dimethylamino)-1-propylamine (0.03 mL,0.22 mmol) and triethylamine (0.04 mL, 0.28 mmol) in 2-propanol (0.5 mL)was heated overnight at 80° C. The reaction mixture was cooled, dilutedwith MeOH (5 mL), and the white precipitate was filtered to yield thetitle compound (172) (14 mg, 17%). LC/MS: Method 4: Rt=1.65 min,m/z=413.2 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Example 150:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 173151

4 50 mg, 58 1.65 399.2 174 152

4 46 mg, 53 1.68 399.2 175 153

4 47 mg, 66 2.10 400.2 176 154

4 48 mg, 60 2.02 373.2 177 155

4 18 mg, 21 1.51 386.2 178 156

4 22 mg, 28 1.52 371.2

Example 157: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(3-(trifluoromethyl)phenyl)urea(180)

Step 1:1-(4-chloro-6-methylpyrimidin-2-yl)-3-(3-(trifluoromethyl)phenyl)urea(179)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (2.6 g, 17.6 mmol) and3-trifluoromethylphenyl isocyanate (3.9 g, 17.6 mmol) in toluene (31 mL)was refluxed overnight. On cooling the suspension was filtered, washedwith MeOH and Et₂O and dried to yield compound (179) (4.4 g, 72%) as awhite solid. LC/MS: Method 4: Rt=3.65 min, m/z=331.1 [MH⁺].

Step 2:1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(3-(trifluoromethyl)phenyl)urea(180)

A mixture of1-(4-chloro-6-methylpyrimidin-2-yl)-3-(3-(trifluoromethyl)phenyl)urea(179) (100 mg, 0.29 mmol), and 3-(dimethylamino)-1-propylamine (0.04 mL,0.34 mmol) and triethylamine (0.06 mL, 0.43 mmol) in 2-propanol (0.5 mL)was heated for 2 hours at 80° C. The reaction mixture was cooled and thewhite precipitate was filtered to yield the title compound (180) (61 mg,54%). LC/MS: Method 4: Rt=1.46 min, m/z=397.2 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Example 157:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 181158

4 200 mg, 76 2.10 384.2 182 159

4 105 mg, 40 1.64 355.2 183 160

4 148 mg, 53 2.04 400.2 184 161

4 145 mg, 59 1.96 356.2 185 162

4 208 mg, 81 2.05 370.2 186 163

4 135 mg, 46 2.51 405.2 187 164

4 192 mg, 69 1.87 386.2 188 165

4  54 mg, 18 2.21 406.2 189 166

4  54 mg, 47 1.67 383.2 190 167

4  56 mg, 46 1.62 383.2 191 168

4 16 mg, 9 1.56 411.2 192 169

4 20 mg, 9 1.59 369.2

Step 1: tert-butylmethyl(3-((6-methyl-2-(3-(3-(trifluoromethyl)phenyl)ureido)pyrimidin-4-yl)amino)propyl)carbamate(193)

A mixture of1-(4-chloro-6-methylpyrimidin-2-yl)-3-(3-(trifluoromethyl)phenyl)urea(179) (189 mg, 0.54 mmol) and 2-propanol (5 mL) was treated withN-(3-aminopropyl)-N-methyl carbamic acid tert-butyl ester (0.13 g, 0.65mmol), and triethylamine (0.11 mL, 0.81 mmol) and this was heated toreflux with stirring for 30 minutes. Upon cooling the precipitate formedwas filtered and washed with MeOH and Et₂O to give the title compound(193) (122 mg, 44%). LC/MS: Method 4: Rt 2.90 min, m/z=483.3 [MH⁺].

Step 2:1-(4-methyl-6-((3-(methylamino)propyl)amino)pyrimidin-2-yl)-3-(3-(trifluoromethyl)phenyl)urea

The BOC derivative (193) (122 mg, 0.24 mmol) was suspended in DCM (5 mL)to which trifluoroacetic acid (0.46 mL, 6.0 mmol) was added. After 15minutes at room temperature the solvent was evaporated and the residuetreated with DCM and 1N sodium hydroxide solution (0.24 mL). The titleproduct was filtered as a white solid (194), washed with water and dried(60 mg, 62%) LC/MS: Method 4: Rt 1.55 min, m/z=383.2 [MH⁺].

Example 171: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethyl)phenyl)urea(196)

Step 1:1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethyl)phenyl)urea(195)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (0.82 g, 5.7 mmol) and4-trifluoromethylphenyl isocyanate (0.91 mL, 6.3 mmol) inN,N-dimethylacetamide (7.6 mL) was heated at 100° C. for 20 minutes. Oncooling the mixture was diluted with MeOH (20 mL). The slurry wasfiltered and washed with MeOH and dried to yield compound 195) (0.98 g,52%) as a white solid.

Step 2:1-(4-((3-(Dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethyl)phenyl)urea(196)

A mixture of1-(4-chloro-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethyl)phenyl)urea(195) (75 mg, 0.23 mmol), and 3-(dimethylamino)-1-propylamine (0.03 mL,0.27 mmol) and triethylamine (0.05 mL, 0.34 mmol) in 2-propanol (0.5 mL)was heated overnight at 80° C. The reaction mixture was cooled and thewhite precipitate was filtered to yield the title compound (196) (8 mg,8%). LC/MS: Method 4: Rt=1.70 min m/z=397.2 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Example 171:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 197172

4 16 mg, 19 2.02 383.2 198 173

4 26 mg, 31 2.01 371.2 199 174

4 26 mg, 29 1.98 401.2 200 175

4 60 mg, 83 2.07 384.2 201 176

4 53 mg, 65 1.93 356.2 202 177

4 55 mg, 66 2.46 354.2 203 178

4 26 mg, 30 1.67 384.2 204 179

4 12 mg, 14 2.07 369.2 205 180

4 6 mg, 6 1.81 398.2 206 181

4 28 mg, 38 1.68 423.3 207 182

4 16 mg, 9  1.69 355.2

Example 183: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(m-tolyl)urea(209)

Step 1: 1-(4-Chloro-6-methyl-2-pyrimidinyl)-3-(3-methylphenyl)urea (208)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (10 g, 68 mmol) and3-methylphenyl isocyanate (11.1 g, 83 mmol) in N,N-dimethylacetamide (50mL) was stirred at room temperature for 1 hour then heated for 2 hoursat 70° C. Upon cooling the mixture was stirred overnight. The slurrywhich formed was filtered, washed with ethanol and dried to yieldcompound (208) (8.0 g, 43%) as a white solid. LC/MS: Method 4: Rt=0.25min, m/z=277.1 [MH⁺].

Step 2:1-(4-((3-(Dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(m-tolyl)urea(209)

1-(4-Chloro-6-methyl-2-pyrimidinyl)-3-(3-methoxyphenyl)urea (208) (0.2g, 0.70 mmol), and 3-(dimethylamino)-1-propylamine (0.11 mL, 0.81 mmol)and triethylamine (0.15 mL, 1.1 mmol) in 2-propanol (1.2 mL) was heatedovernight at 70° C. The reaction mixture was cooled and filtered. Thesolids were washed with ethanol to yield the title compound (209) (0.19g, 77%). LC/MS: Method 4: Rt=0.35 min, m/z=343.3 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Example 183:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 210184

4 159 mg, 72 1.29 315.2 211 185

4 185 mg, 88 1.56 302.2 212 186

4 170 mg, 74 1.20 330.2 213 187

4  65 mg, 31 0.36 301.2 214 188

4 115 mg, 59 0.34 369.3 215 189

4  50 mg, 22 0.35 329.3 216 190

4 225 mg, 98 0.34 329.2 217 191

4 108 mg, 45 1.64 346.2 218 192

4 156 mg, 74 2.07 300.2 219 193

4 190 mg, 86 1.69 316.2 220 194

4 100 mg, 39 2.00 344.2 221 195

4 195 mg, 70 1.41 377.3 222 196

4 195 mg, 75 2.26 351.2 223 197

4 195 mg, 80 1.57 332.2 224 198

4 110 mg, 52 1.90 286.2 225 199

4 14 mg, 7 1.37 352.2 226 200

4 120 mg, 59 1.32 366.2 227 201

4 130 mg, 52 1.29 357.3

Example 202: Synthesis of1-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)-3-(m-tolyl)urea(229)

Step 1: tert-Butylmethyl(2-((6-methyl-2-(3-(m-tolyl)ureido)pyrimidin-4-yl)amino)ethyl)carbamate(228)

A mixture of 1-(4-chloro-6-methylpyrimidin-2-yl)-3-(m-tolyl)urea (208)(200 mg, 0.70 mmol) and 2-propanol (1.2 mL) was treated withN-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (1.2 mL, 16.7mmol), and triethylamine (0.15 mL, 1.1 mmol) and this was heated toreflux with stirring overnight. Upon cooling, the mixture was filteredand the solids washed with ethanol to give the title compound (228) (240mg, 83%). LC/MS: Method 4: Rt=0.33 min, m/z=415.3 [MH⁺].

Step 2:1-(4-Methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)-3-(m-tolyl)urea(229)

The BOC derivative (228) (226 mg, 0.53 mmol) was suspended in DCM (0.7mL) to which trifluoroacetic acid (0.7 mL, 9 mmol) was added. After 2hours at room temperature the mixture was treated with saturated sodiumbicarbonate solution to achieve a pH of 8. The title product wasfiltered as a white solid (229) (165 mg, 100%). LC/MS: Method 4: Rt=0.35min, m/z=315.2 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Example 202:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 230203

4 180 mg, 81 0.35 329.3 231 204

4 120 mg, 46 1.29 343.3 232 205

4 200 mg, 78 1.25 355.3

Example 206: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(p-tolyl)urea(234)

Step 1: 1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(p-tolyl)urea (233)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (3 g, 20 mmol) and4-methylphenyl isocyanate (3.3 g, 25 mmol) in N, N-dimethylacetamide (15mL) was stirred at room temperature for 1 hour, heated for 2 hours at70° C., then maintained at 50° C. overnight. Upon cooling the mixturewas stirred overnight. The slurry which formed was filtered, washed withethanol and dried to yield compound (233) (3.3 g, 59%) as a white solid.LC/MS: Method 4: Rt=3.28 min, m/z=277.1 [MH⁺].

Step 2:1-(4-((3-(Dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(p-tolyl)urea(234)

1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(p-tolyl)urea (233) (0.2 g, 0.70mmol), and 3-(dimethylamino)-1-propylamine (0.11 mL, 0.81 mmol) andtriethylamine (0.15 mL, 1.1 mmol) in 2-propanol (1.2 mL) was heatedovernight at 70° C. The reaction mixture was cooled and filtered. Thesolids were washed with ethanol to yield the title compound (234) (0.19g, 77%). LC/MS: Method 4: Rt=1.32 min, m/z=343.3 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Example 206:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 235207

4 195 mg, 75 2.21 351.2 236 208

4 155 mg, 70 1.12 315.2 237 209

4 150 mg, 68 1.12 301.2 238 210

4 193 mg, 80 1.66 346.2 239 211

4 185 mg, 76 1.70 330.2 240 212

4 144 mg, 68 1.61 302.2 241 213

4 150 mg, 65 1.30 329.2 242 214

4 108 mg, 45 1.69 330.2 243 215

4  25 mg, 12 1.31 366.2 244 216

4  40 mg, 21 1.27 352.2 245 217

4  80 mg, 32 1.38 357.3 246 218

4 140 mg, 57 1.57 332.2

Example 219: Synthesis of1-(4-methyl-6-((3-(methylamino)propyl)amino)pyrimidin-2-yl)-3-(p-tolyl)urea(248)

Step 1: tert-Butylmethyl(3-((6-methyl-2-(3-(p-tolyl)ureido)pyrimidin-4-yl)amino)propyl)carbamate(247)

A mixture of 1-(4-chloro-6-methylpyrimidin-2-yl)-3-(p-tolyl)urea (233)(200 mg, 0.70 mmol) and 2-propanol (0.96 mL) was treated withN-(3-aminopropyl)-N-methyl carbamic acid tert-butyl ester (0.1 mL, 0.84mmol), and triethylamine (0.15 mL, 1.1 mmol) and this was heated to 70°C. with stirring overnight. Upon cooling, the precipitate formed wasdried to give the title compound (247) (164 mg, 53%).

Step 2:1-(4-Methyl-6-((3-(methylamino)propyl)amino)pyrimidin-2-yl)-3-(p-tolyl)urea(248)

The BOC derivative (247) (251 mg, 0.56 mmol) was suspended in DCM (0.75mL) to which trifluoroacetic acid (0.71 mL, 9.7 mmol) was added. After 2hours at room temperature the solvent was evaporated and the residuetreated with saturated sodium bicarbonate solution sufficient to achievea pH of 8. The title product was filtered as a white solid (248), washedwith water and dried (160 mg, 82%). LC/MS: Method 4: Rt 1.22 min,m/z=329.2 [MH⁺].

Example 220: Synthesis of1-(4-methyl-6-((piperidin-3-ylmethyl)amino)pyrimidin-2-yl)-3-(p-tolyl)urea(249)

Example 220 was prepared in a similar manner to example 219 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(p-tolyl)urea (233) and tert-butyl3-(aminomethyl)piperidine-1-carboxylate. (180 mg, 71%) LC/MS: Method 4:Rt=1.31 min, m/z=355.3 [MH+].

Example 221: Synthesis of1-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(3,4-dimethylphenyl)urea(251)

Step 1: 1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(3,4-dimethylphenyl)urea(250)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (10 g, 68 mmol) and 3,4-dimethylphenyl isocyanate (12.3 g, 83 mmol) in N, N-dimethylacetamide(60 mL) was stirred at room temperature for 1 hour then heated overnightat 50° C. Upon cooling the mixture was stirred overnight. The slurrywhich formed was filtered, washed with ether and dried to yield compound(250) (4.8 g, 24%) as a white solid. LC/MS: Method 4: Rt=0.25 min,m/z=277.1 [MH⁺]. This material was used directly in the next step.

Step 2:1-(4-((3-(Dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)-3-(3,4-dimethylphenyl)urea(251)

1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(3,4-dimethylphenyl)urea (250)(0.2 g, 0.67 mmol), and 3-(dimethylamino)-1-propylamine (0.11 mL 0.81mmol) and triethylamine (0.14 mL, 1.0 mmol) in 2-propanol (1.1 mL) washeated overnight at 70° C. The reaction mixture was cooled and filtered.The solids were washed with ethanol to yield the title compound (251)(198 mg, 83%). LC/MS: Method 4: Rt=0.35 min, m/z=357.3 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Example 221:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 252222

4 85 mg, 31 0.36 301.2 253 223

4 50 mg, 23 2.07 329.2 254 224

4 39 mg, 17 2.10 343.3 255 225

4 42 mg, 18 2.66 344.2 256 226

4 75 mg, 30 0.38 371.3 257 227

4 50 mg, 22 0.35 329.3 258 228

4 20 mg, 10 0.40 383.3 259 229

4 38 mg, 24 2.34 316.2 260 230

4 91 mg, 38 1.82 360.2 261 231

4 127 mg, 61  0.33 314.2 262 232

4 130 mg, 56  1.29 330.2 263 233

4 195 mg, 76  2.44 365.3 264 234

4 195 mg, 81  1.75 346.2 265 235

4 25 mg, 13 1.62 366.2 266 236

4 20 mg, 10 1.50 380.2

Example 237: Synthesis of1-(3,4dimethylphenyl)-3-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)urea(268)

Step 1: tert-Butyl(2-((2-(3-(3,4-dimethylphenyl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)(methyl)carbamate(267)

A mixture of1-(4-chloro-6-methylpyrimidin-2-yl)-3-(3,4-dimethylphenyl)urea (250)(200 mg, 0.70 mmol) and 2-propanol (1.2 m) was treated withN-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (1.2 mL, 16.7mmol), and triethylamine (0.15 mL, 1.1 mmol) and this was heated toreflux with stirring overnight. Upon cooling, the mixture was filteredand the solids washed with ethanol to give the title compound (267) (168mg, 59%).

Step 2:1-(3,4-Dimethylphenyl)-3-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)urea(268)

The BOC derivative (267) (167 mg, 0.38 mmol) was suspended in DCM (0.5mL) to which trifluoroacetic acid (0.48 mL, 6 mmol) was added. After 2hours at room temperature the mixture was treated with saturated sodiumbicarbonate solution to achieve a pH of 8. The title product wasfiltered as a white solid (268) (115 mg, 93%). LC/MS: Method 4: Rt=0.37min, m/z=329.2 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Example 237:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 269238

4 100 mg, 50 0.37 343.2 270 239

4  84 mg, 37 0.36 357.3 271 240

4 109 mg, 45 0.35 369.3

Example 241: Synthesis ofN-(3-((2-(3-(3,4-dichlorophenyl)ureido)-6-methylpyrimidin-4-yl)amino)propyl)acetamide(272)

A mixture of1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(3,4-dichlorophenyl)urea(9) (100 mg, 0.27 mmol), acetic anhydride (0.03 mL, 0.29 mmol), pyridine(0.14 mL, 1.7 mmol) and a catalytic amount of N,N-dimethylaminopyridinein DCM (0.54 mL) was stirred at room temperature for 2.5 hours. At thistime the mixture was cooled to −20° C. before dilution with MeOH (5 mL).The resulting solids were filtered and dried to yield the title product(272) (75 mg, 64%). LC/MS: Method 4: Rt=2.07 min, m/z=411.2-413.2 [MH⁺].

Example 242: Synthesis ofN-(3-((6-methyl-2-(3-(4-(trifluoromethoxy)phenyl)ureido)pyrimidin-4-yl)amino)propyl)acetamide(273)

Example 242 was prepared by a similar procedure to that described forexample 241 from1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(3-(trifluoromethoxy)phenyl)urea(89) (11 mg, 20%). LC/MS: Method 4: Rt=2.02 min, m/z=427.2 [MH⁺].

Example 243: Synthesis ofN-(3-((6-methyl-2-(3-(4-(trifluoromethoxy)phenyl)ureido)pyrimidin-4-yl)amino)ethyl)acetamide(274)

Example 243 was prepared by a similar procedure to that described forexample 241 from1-(4-((3-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(87) (11 mg, 20%). LC/MS: Method 4: Rt=2.02 min, m/z=427.2 [MH⁺].

Example 244: Synthesis ofN-(3-((2-(3-(4-methoxyphenyl)ureido)-6-methylpyrimidin-4-yl)amino)propyl)acetamide(275)

Example 244 was prepared by a similar procedure to that described forexample 241 from1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(4-methoxyphenyl)urea(131) (47 mg, 56%). LC/MS: Method 4: Rt=1.44 min, m/z=373.2 [MH⁺].

Example 245: Synthesis ofN-(2-((2-(3-(4-methoxyphenyl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)acetamide(276)

Example 245 was prepared by a similar procedure to that described forexample 241 from1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(4-methoxyphenyl)urea(127) (19 mg, 49%). LC/MS: Method 4: Rt=1.37 min, m/z=359.2 [MH⁺].

Example 246: Synthesis ofN-(2-((2-(3-(4-methoxyphenyl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)acetamide(277)

Example 246 was prepared by a similar procedure to that described forexample 241 from1-(4-((2-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(3-(trifluoromethyl)phenyl)urea(182) (12 mg, 33%). LC/MS: Method 4: Rt=1.87 min, m/z=397.2 [MH⁺].

Example 247: Synthesis ofN-(3-((2-(3-(3-chloro-4-fluorophenyl)ureido)-6-methylpyrimidin-4-yl)amino)propyl)acetamide(278)

Example 247 was prepared by a similar procedure to that described forexample 241 from1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(3-chloro-4-fluorophenyl)urea(158) (24 mg, 43%). LC/MS: Method 4: Rt=1.83 min, m/z=395.2 [MH⁺].

Example 248: Synthesis ofN-(2-((6-methyl-2-(3-(4-(trifluoromethoxy)phenyl)-ureido)-pyrimidin-4-yl)-ethyl)methanesulfonamide(279)

To a mixture of1-(4-((3-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(4-(trifluoromethoxy)phenyl)urea(87), (53 mg, 0.14 mmol) and triethylamine (0.04 mL, 0.28 mmol) in DCM(0.48 mL) that was cooled to 0° C. was added, methanesulfonyl chloride(0.01 mL, 0.16 mmol), and this was stirred at room temperature for 5hours. At this time the mixture was diluted with MeOH (5 mL) and theresulting solids filtered. This material was purified by silica gelchromatography using a gradient of 0-10% MeOH in DCM. Evaporation of theappropriate fractions afforded the title product (279) (5 mg, 7%).LC/MS: Method 4: Rt=2.14 min, m/z=449.1 [MH+].

Example 249: Synthesis of1-(benzo[d][1,3]dioxol-5-yl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)urea(281)

Step 1:1-(Benzo[d][1,3]dioxol-5-yl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea(280)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (0.51 g, 3.5 mmol) and2H-benzo[d]1,3-dioxolan-5-isocyanate (0.64 g, 3.9 mmol) in toluene (4.7mL) was heated with stirring for 2 hours at 100° C., then at 50° C.overnight. Upon cooling, the mixture was diluted with methanol (10 mL)and the slurry which formed was filtered, triturated with methanol anddried to yield compound (280) (0.48 g, 44%). This material was useddirectly in the next step.

Step 2:1-(Benzo[d][1,3]dioxol-5-yl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)urea(281)

A mixture of1-(benzo[d][1,3]dioxol-5-yl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea(280) (0.1 g, 0.33 mmol), and 3-(dimethylamino)-1-propylamine (0.05 mL,0.40 mmol) and triethylamine (0.07 mL, 0.5 mmol) in 2-propanol (0.66 mL)was heated overnight at 80° C. The reaction mixture was cooled andfiltered and this solid was purified by preparative TLC eluting with 30%1M NH₄OH in MeOH/70% DCM to yield the title compound (281) (27 mg, 31).LC/MS: Method 4: Rt=0.98 min, m/z=373.2 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Example 249:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 282250

4 12 mg, 18 0.99 345.2 283 251

4 23 mg, 31 0.93 331.2 284 252

4 33 mg, 40 1.10 359.2 285 253

4 59 mg, 76 1.68 316.2 286 254

4 65 mg, 81 1.85 330.2

Example 255: Synthesis of1-(benzo[d]1,3dioxol-5-yl)-3-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)urea(288)

Step 1: tert-Butyl(2-((2-(3-(benzo[d][1,3]dioxol-5-yl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)(methyl)carbamate(287)

A mixture of1-(benzo[d][1,3]dioxol-5-yl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea(280) (82 mg, 0.27 mmol) and 2-propanol (0.5 mL) was treated withN-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (0.06 mL, 0.32mmol), and triethylamine (0.06 mL, 0.40 mmol) and this was heated to 80°C. with stirring overnight. Upon cooling the reaction was diluted withMeOH (3 mL) and the precipitate formed was filtered to give the titlecompound (287) (85 mg, 72%). LC/MS: Method 4: Rt=2.14 min, m/z=445.3[MH⁺].

Step 2:1-(Benzo[d][1,3]dioxol-5-yl)-3-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)urea

The BOC derivative (287) (85 mg, 0.19 mmol) was suspended in DCM (0.15mL) to which trifluoroacetic acid (0.14 mL, 1.9 mmol) was added. After40 minutes at room temperature the solvent was evaporated and theresidue treated with saturated sodium bicarbonate solution to achieve apH of 8. The title product was filtered and washed with water to yield awhite solid (288) after drying (30 mg, 46%). LC/MS: Method 4: Rt=0.94min, m/z=345.2 [MH⁺].

Example 256: Synthesis of1-(benzo[d][1,3]dioxol-5-yl)-3-(4-methyl-6-((3-(methylamino)propyl)amino)pyrimidin-2-yl)urea(289)

Example 262 was prepared in a similar manner to example 261 from1-(benzo[d][1,3]dioxol-5-yl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea(287) and N-(3-aminopropyl)-N-methyl carbamic acid tert-butyl ester. (17mg, 19%) LC/MS: Method 4: Rt=1.01 min, m/z=359.2 [MH⁺].

Example 257: Synthesis of1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)urea(291)

Step 1:1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)urea(290)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (2.1 g, 15 mmol) and2H, 3H-benzo[e]1,4-dioxan-6-isocyanate (3 g, 16 mmol) in toluene (19.9mL) was heated with stirring for 1 hour at 100° C., then at 50° C.overnight. Upon cooling the mixture was diluted with methanol (20 mL)and the slurry which formed was filtered, triturated with methanol anddried to yield compound (290) (2.8 g, 59%). This material was useddirectly in the next step.

Step 2:1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)urea(291)

A mixture of1-(4-chloro-6-methylpyrimidin-2-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)urea(290) (75 mg, 0.23 mmol), and 3-(dimethylamino)-1-propylamine (0.04 mL,0.28 mmol) and triethylamine (0.05 mL, 0.35 mmol) in 2-propanol (0.47mL) was heated for 5 hours at 80° C. The reaction mixture was cooled andfiltered and this solid was purified by preparative TLC eluting with 30%1M NH₄₀H in MeOH/70% DCM to yield the title compound (291) (17 mg, 19%).LC/MS: Method 4: Rt=1.04 min, m/z=387.3 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Example 257:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 292258

4 185 mg, 83  0.91 359.2 293 259

4 188 mg, 87  1.02 345.2 294 260

4 47 mg, 54 1.14 373.2 295 261

4 58 mg, 75 1.60 330.2 296 262

4 68 mg, 85 1.78 344.2

Example 263: Synthesis of1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)urea(298)

Step 1: tert-Butyl(2-((2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ureido)-6-methylpyrimidin-4-yl)amino)ethyl)(methyl)carbamate(297)

A mixture of1-(4-chloro-6-methylpyrimidin-2-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)urea(290) (75 mg, 0.23 mmol) and 2-propanol (0.48 mL) was treated withN-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (0.05 mL, 0.28mmol), and triethylamine (0.05 mL, 0.35 mmol) and this was heated to 80°C. with stirring overnight. Upon cooling, the reaction was diluted withMeOH (3 mL) and the precipitate formed was filtered and further washedwith MeOH to give the title compound (297) (76 mg, 70%). LC/MS: Method4: Rt=2.10 min, m/z=459.3 [MH⁺].

Step2:1-(benzo[d][1,3]dioxol-5-yl)-3-(4-methyl-6-((2-(methylamino)ethyl)amino)pyrimidin-2-yl)urea

The BOC derivative (297) (76 mg, 0.16 mmol) was suspended in DCM (0.1mL) to which trifluoroacetic acid (0.12 mL, 1.6 mmol) was added. After3.5 hours at room temperature the solvent was evaporated and the residuetreated with saturated sodium bicarbonate solution to achieve a pH of 8.The title product was filtered and washed with water to yield a whitesolid (298) after drying. (42 mg, 71%) LC/MS: Method 4: Rt=1.03 min,m/z=359.2 [MH⁺].

Example 264: Synthesis of1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(4-methyl-6-((3-(methylamino)propyl)amino)pyrimidin-2-yl)urea(299)

Example 262 was prepared in a similar manner to example 261 from1-(4-chloro-6-methylpyrimidin-2-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)urea(290) and N-(3-aminopropyl)-N-methyl carbamic acid tert-butyl ester. (57mg, 64%) LC/MS: Method 4: Rt=1.03 min, m/z=373.2 [MH⁺].

Example 265: Synthesis of1-(4-(tert-butyl)phenyl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)urea(301)

Step 1: 1-(4-(tert-Butyl)phenyl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea(300)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (2.0 g, 14 mmol) and4-tert-butylphenyl isocyanate (2.9 g, 16 mmol) in toluene (12.7 mL) wasstirred for 1 hour at room temperature, then heated at 110° C.overnight. Upon cooling the slurry which formed was filtered, washedwith ether and dried to yield compound (300) (2.3 g, 53%). This materialwas used directly in the next step.

Step 2:1-(4-(tert-Butyl)phenyl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)urea(301)

A mixture of1-(4-(tert-butyl)phenyl)-3-(4-chloro-6-methylpyrimidin-2-yl)urea (300)(100 mg, 0.30 mmol), and 3-(dimethylamino)-1-propylamine (0.05 mL, 0.36mmol) and triethylamine (0.06 mL, 0.45 mmol) in 2-propanol (0.5 mL) washeated for 2 hours at 80° C. The reaction mixture was cooled andfiltered to yield the title compound (301) (80 mg, 66%). LC/MS: Method4: Rt=1.72 min, m/z=385.3 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Example 265:

Cpd Example Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 302 266

4 95 mg, 78 1.65 371.3 303 267

4 80 mg, 34 1.64 357.3 304 268

4 183 mg, 85  1.67 343.2

Example 269: Synthesis ofN-(3-((2-(3-(benzo[d][1,3]dioxol-5-yl)ureido)-6-methylpyrimidin-4-yl)amino)propyl)acetamide(305)

A mixture of1-(4-((3-aminopropyl)amino)-6-methylpyrimidin-2-yl)-3-(benzo[d][1,3]dioxol-5-yl)urea(282) (75 mg, 0.22 mmol), acetic anhydride (0.02 mL, 0.24 mmol),pyridine (0.11 mL, 1.3 mmol) and a catalytic amount ofN,N-dimethylaminopyridine in DCM (0.44 mL) was stirred at roomtemperature for 2 hours. At this time another aliquot of aceticanhydride (0.01 mL) was added and stirring continued overnight. Themixture was diluted with DCM (3 mL) and the resulting solids werefiltered and dried to yield the title product (305) (39 mg, 47%). LC/MS:Method 4: Rt=1.45 min, m/z=387.2 [MH⁺].

Example 270: Synthesis ofN-{2-[2-(3-benzo[1,3]dioxol-5-yl-ureido)-6-methyl-pyrimidin-4-ylamino]-ethyl}-acetamide(306)

A mixture of1-[4-(2-amino-ethylamino)-6-methyl-pyrimidin-2-yl]-3-benzo[1,3]dioxol-5-yl-urea(283) (75 mg, 0.23 mmol), acetic anhydride (0.02 mL, 0.25 mmol),pyridine (0.11 mL, 1.4 mmol) and a catalytic amount ofN,N-dimethylaminopyridine in DCM (0.44 mL) was stirred at roomtemperature for 1 hour. The mixture was diluted with DCM (3 mL) and theresulting solids were filtered and dried to yield the title product(306) (63 mg, 74%). LC/MS: Method 4: Rt=1.34 min, m/z=373.2 [MH⁺].

Example 271: Synthesis ofN-(2-{2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ureido]-6-methyl-pyrimidin-4-ylamino}-ethyl)-acetamide(307)

Example 271 was prepared by a similar procedure to that described forexample 270 from1-[4-(2-Amino-ethylamino)-6-methyl-pyrimidin-2-yl]-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-urea(293) (36 mg, 43%). LC/MS: Method 4: Rt=1.43 min, m/z=387.2 [MH⁺].

Example 272: Synthesis ofN-(3-{2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ureido]-6-methyl-pyrimidin-4-ylamino}-propyl)-acetamide(308)

Example 272 was prepared by a similar procedure to that described forexample 270 from1-[4-(3-amino-propylamino)-6-methyl-pyrimidin-2-yl]-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-urea(292) (58 mg, 69%). LC/MS: Method 4: Rt=1.49 min, m/z=401.2 [MH⁺].

Example 273: Synthesis ofN-(2-{2-[3-(4-tert-butyl-phenyl)-ureido]-6-methyl-pyrimidin-4-ylamino}-ethyl)-acetamide(309)

Example 273 was prepared by a similar procedure to that described forexample 270 from1-[4-(2-amino-ethylamino)-6-methyl-pyrimidin-2-yl]-3-(4-tert-butyl-phenyl)-urea(293) except the mixture was diluted with Et₂O (5 mL) prior tofiltration of the solid product (40 mg, 21%). LC/MS: Method 4: Rt=2.15min, m/z=385.3 [MH⁺].

Example 274: Synthesis ofN-(3-{2-[3-(4-tert-butyl-phenyl)-ureido]-6-methyl-pyrimidin-4-ylamino}-propyl)-acetamide(310)

Example 274 was prepared by a similar procedure to that described forexample 270 from1-[4-(3-amino-propylamino)-6-methyl-pyrimidin-2-yl]-3-(4-tert-butyl-phenyl)-urea(303) except the mixture was diluted with Et₂O (5 mL) prior tofiltration of the solid product (40 mg, 21%). LC/MS: Method 4: Rt=2.22min, m/z=399.3 [MH⁺].

Example 275: Synthesis of N-2-(3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ureido)-6-methyl-pyrimidin-4-yl)-ethyl)methanesulfonamide(311)

To a mixture of1-(4-((3-aminoethyl)amino)-6-methylpyrimidin-2-yl)-3-(3-(trifluoromethoxy)phenyl)urea(87), (53 mg, 0.14 mmol) and triethylamine (0.04 mL, 0.28 mmol) in DCM(0.48 mL) that was cooled to 0° C. was added, methanesulfonyl chloride(0.01 mL, 0.16 mmol), and this was stirred at room temperature for 5hours. At this time the mixture was diluted with MeOH (5 mL) and theresulting solids filtered. This material was purified by silica gelchromatography using a gradient of 0-10% MeOH in DCM. Evaporation of theappropriate fractions afforded the title product (311) (5 mg, 7%).LC/MS: Method 4: Rt=2.14 min, m/z=449.1 [MH+].

Example 276: Synthesis of1-(2,3-dihydro-1H-inden-5-yl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)urea(313)

Step 1:1-(4-Chloro-6-methylpyrimidin-2-yl)-3-(2,3-dihydro-1H-inden-5-yl)urea(312)

A mixture of 2-amino-4-chloro-6-methylpyrimidine (1.5 g, 10 mmol) and5-indanyl isocyanate (2.0 g, 12 mmol) in toluene (9.5 mL) was stirred atroom temperature for 1 hour then heated overnight at 110° C. Uponcooling the mixture was stirred overnight. The slurry which formed wasfiltered, washed with ether and dried to yield compound (312) (2.5 g,82%). LC/MS: Method 4: Rt=3.79 min, m/z=303.1 [MH⁺]. This material wasused directly in the next step.

Step 2:1-(2,3-Dihydro-1H-inden-5-yl)-3-(4-((3-(dimethylamino)propyl)amino)-6-methylpyrimidin-2-yl)urea(313)

A mixture of1-(4-chloro-6-methylpyrimidin-2-yl)-3-(2,3-dihydro-1H-inden-5-yl)urea(312) (0.1 g, 0.33 mmol), and 3-(dimethylamino)-1-propylamine (0.05 mL,0.40 mmol) and triethylamine (0.07 mL, 0.5 mmol) in 2-propanol (0.66 mL)was heated for 2 hours at 80° C. The reaction mixture was cooled andfiltered to yield the title compound (313) (90 mg, 70%). LC/MS: Method4: Rt=1.41 min, m/z=369.3 [MH⁺].

The following examples were prepared according to similar proceduresdescribed for Example 276:

Cpd Example HPLC Yield RT ID ID Structure Method (mass/%) (min) MH⁺ 314277

4 80 mg, 74 2.31 326.2 315 278

4 95 mg, 77 1.44 355.3 316 279

4 75 mg, 70 1.37 327.2 317 280

4 80 mg, 68 1.42 341.2 318 281

4 8 mg, 8 2.21 312.2

Example 282: Synthesis ofN-(2-{2-[3-(2,3-dihydro-1H-inden-5-yl)-ureido]-6-methyl-pyrimidin-4-ylamino}-ethyl)-acetamide(319)

A mixture of1-[4-(2-amino-ethylamino)-6-methyl-pyrimidin-2-yl]-3-(2,3-dihydro-1H-inden-5-yl)-urea(316) (62 mg, 0.19 mmol), acetic anhydride (0.02 mL, 0.21 mmol),pyridine (0.10 mL, 1.2 mmol) and a catalytic amount ofN,N-dimethylaminopyridine in DCM (0.38 mL) was stirred at roomtemperature for 3 hours. The mixture was cooled in a freezer thendiluted with diethyl ether (5 mL). The resulting solids were filteredand dried to yield the title product (319) (40 mg, 57%). LC/MS: Method4: Rt=1.87 min, m/z=369.2 [MH+].

Example 283: GBM4 and GBM8 Viability Assay

Cell culture medium was prepared from a NSA proliferation kit(Neurocult) and NeuroCult supplements (Stemcell Tech Cat. #05751) andtreated with 20 μL of 10 μg/mL rh EGF, 10 μL of 10 μg/mL rh bFGF and 10μL of 0.2% Heparin. In this medium, human glioblastoma cells werecultured in ultra-low attachment tissue culture flasks until 1×106 cellsml was achieved (GBM4 and GBM8 are distinct neurosphere cell culturesderived from these human patient tissues). GBM4 and GBM8 cells weredissociated and 10 mL of media containing 4000 human glioblastoma cellsper 90 uL were transferred to an ultra-low binding 96-well plate andincubated at 37° C. overnight. On the following day, 10 μL of a 1% DMSOsolution of test compound in assay medium was added to wells containingthe cell suspension and the mixture incubated at 37° C. for 3 days. Atthis time, the plate was removed from the incubator and allowed to reachroom temperature. After about 30 minutes, 50 μL of Cell Titer Glosolution was added to each well and the plate shaken for 1 minute at lowspeed. After 10 minutes luminescence was recorded using a Tecan Safire2reader.

Reduction in luminescence compared to DMSO only control wells was usedto determine the percentage inhibition of cell growth. IC50s werecalculated using the % inhibition of luminescence for serial dilutionsof compounds fitted to a 4-parameter fit within the Prism (San Diego)curve fitting program. Table 1 below shows the GBM4 IC50 and GBM8 IC50for compounds described herein.

TABLE 1 GBM4 GBM8 IC50 IC50 Cpd # (uM) (uM) 2 NT NT 3 NT NT 4 C B 5 C NT6 B B 7 A A 8 A A 9 NT A 10 NT A 11 NT A 12 NT A 13 NT A 14 NT A 15 NT A16 NT A 17 NT A 18 NT A 19 NT B 20 NT A 21 NT B 22 NT A 24 A A 26 NT A27 NT A 28 NT A 29 NT A 30 C C 34 C B 35 NT A 36 NT A 37 B NT 38 C B 39B B 41 NT A 43 NT A 44 NT A 45 NT A 47 NT A 48 NT B 49 NT A 50 NT A 51NT A 52 NT A 53 NT A 54 NT A 55 NT A 56 NT B 57 NT B 58 NT B 59 NT A 60NT A 61 NT A 63 NT B 64 NT A 65 NT A 66 NT A 67 NT A 69 NT B 70 NT B 71NT B 72 NT B 73 NT B 74 NT B 75 NT B 76 NT B 77 NT B 78 NT A 79 NT B 80NT B 82 NT B 83 NT B 85 NT A 86 NT A 87 NT A 88 NT A 89 NT A 90 NT A 91NT A 92 NT A 93 NT A 94 NT A 95 NT A 96 NT A 98 NT A 99 NT A 101 NT A102 NT A 103 NT A 104 NT A 105 NT A 106 NT A 107 NT A 108 NT A 109 NT A110 NT A 111 NT A 112 NT A 113 NT B 114 NT A 115 NT A 116 NT A 117 NT A118 NT A 120 NT A 121 NT A 122 NT A 123 NT A 125 NT A 126 NT A 127 NT A128 NT A 129 NT A 130 NT A 131 NT A 132 NT A 133 NT A 134 NT B 135 NT A136 NT A 137 NT A 138 NT A 139 NT A 141 NT B 142 NT B 143 NT B 144 NT B145 NT B 146 NT B 147 NT B 148 NT B 149 NT B 150 NT B 151 NT B 153 NT B154 NT B 155 NT B 157 NT A 158 NT A 159 NT B 160 NT A 161 NT A 162 NT A163 NT A 164 NT A 165 NT A 166 NT A 167 NT B 169 NT A 170 NT A 172 NT A173 NT A 173 NT A 174 NT B 175 NT A 176 NT A 177 NT A 178 NT A 180 NT A181 NT A 182 NT A 183 NT B 184 NT A 185 NT A 186 NT A 187 NT A 188 NT A189 NT B 190 NT A 191 NT A 192 NT A 194 NT A 196 NT A 197 NT A 198 NT A199 NT A 200 NT A 201 NT A 202 NT A 203 NT A 204 NT B 205 NT B 206 NT B207 NT A 209 NT A 210 NT A 211 NT A 212 NT A 213 NT A 214 NT B 215 NT A216 NT A 217 NT A 218 NT A 219 NT A 220 NT B 221 NT B 222 NT A 223 NT A224 NT A 225 NT A 226 NT A 227 NT A 229 NT B 230 NT A 231 NT B 232 NT A234 NT A 235 NT A 236 NT A 237 NT A 238 NT B 239 NT A 240 NT A 241 NT A242 NT B 243 NT A 244 NT B 245 NT B 246 NT A 248 NT B 249 NT B 251 NT A252 NT A 253 NT A 254 NT A 255 NT A 256 NT A 257 NT A 258 NT B 259 NT A260 NT B 261 NT A 262 NT A 263 NT A 264 NT A 265 NT A 266 NT A 268 NT B269 NT A 270 NT A 271 NT A 272 NT B 273 NT A 274 NT A 275 NT A 276 NT A277 NT B 278 NT A 279 NT A 281 NT B 282 NT A 283 NT A 284 NT B 285 NT A286 NT A 288 NT A 289 NT B 291 NT A 292 NT A 293 NT B 294 NT A 295 NT A296 NT A 298 NT A 299 NT B 301 NT A 302 NT B 303 NT A 304 NT A 305 NT A306 NT B 307 NT A 308 NT A 309 NT A 310 NT A 311 NT A IC50: A <1 μM; 1μM ≤ B ≤ 10 μM; 10 μM < C ≤ 30 μM; NT = not tested

Example 284: Phase II Clinical Trial of Compounds of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI) in Patients withRecurrent Rb Positive Glioblastoma

The purpose of this phase II trial is to determine the efficacy of acompound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV),(V) or (VI) (as measured by progression free survival at 6months) inpatients with recurrent glioblastoma multiforme or gliosarcoma who areRb positive. A total of 30 patients will be treated; 15 will undergo aplanned surgical resection and receive drug for 7 days prior to surgery,followed by drug after recovery from surgery, and the other 15 patientswill receive drug without a planned surgical procedure.

Patients: Eligible Subjects Will be Men and Women 18 Years and Older

Criteria:

Inclusion Criteria:

-   -   Patients with radiographically proven recurrent, intracranial        Glioblastoma multiforme or Gliosarcoma will be eligible for this        protocol. Patients must have documentation of Rb positive        disease.    -   All patients must sign an informed consent indicating that they        are aware of the investigational nature of this study. Patients        must have signed an authorization for the release of their        protected health information. Patients must be registered prior        to treatment with study drug. Treatment must take place within 7        days of registration; if treatment is delayed more than 7 days,        the laboratory tests for eligibility and history and physical        exam must be repeated.    -   Patients must have had prior external beam radiation and        temozolomide chemotherapy; there is no limit to the number of        prior chemotherapies used; patients may be treated in their        first, second or third relapse    -   Patients must be >18 years old, and with a life expectancy >8        weeks.    -   Patients must have a Karnofsky Performance Status of >60.    -   At the time of registration: Patients must have recovered from        the toxic effects of prior therapy: >28 days from any        investigational agent [NOTE: off-label use of FDA approved        agents are not considered investigational for the purposes of        this protocol], >28 days from prior cytotoxic therapy, >42 days        from nitrosoureas, >28 days from bevacizumab, and >7 days for        non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide,        cis-retinoic acid, and erlotinib, for example. Any questions        related to the definition of non-cytotoxic agents should be        directed to the Study Chair.    -   Patients must have adequate bone marrow function (WBC >³,000/μl,        ANC >1,500/mm3, platelet count of >100,000/mm3, and        hemoglobin >10 gm/dl), adequate liver function (SGOT and        bilirubin <2 times ULN), and adequate renal function (creatinine        <1.5 mg/dL) before starting therapy. A pre-study EKG is required        for all patients, and patients must have a normal QT interval.        These tests must be performed within 14 days prior to        registration. Eligibility level for hemoglobin may be reached by        transfusion.    -   Patients must have shown unequivocal radiographic evidence for        tumor progression by MRI scan. A scan should be performed within        14 days prior to registration and on a steroid dose that has        been stable for at least 7 days. If the steroid dose is        increased between the date of imaging and registration a new        baseline MRI is required. The same type of scan, i.e., MRI must        be used throughout the period of protocol treatment for tumor        measurement. Patients unable to undergo MR imaging will not be        eligible.    -   Patients having undergone recent resection of recurrent or        progressive tumor will be eligible as long as all of the        following conditions apply:        -   They have recovered from the effects of surgery.        -   Residual disease following resection of recurrent            intracranial Glioblastoma Multiforme or Gliosarcoma is not            mandated for eligibility into the study. To best assess the            extent of residual disease post-operatively, an MRI should            be done no later than 96 hours in the immediate            post-operative period or at least 4 weeks post-operatively,            within 14 days prior to registration. If the 96-hour scan is            more than 14 days before registration, the scan needs to be            repeated. If the steroid dose is increased between the date            of imaging and registration, a new baseline MRI is required            on a stable steroid dosage for at least 7 days.    -   Patients must have failed prior radiation therapy and        temozolomide and must have an interval of greater than or equal        to 42 days from the completion of radiation therapy to study        entry.    -   Patients with prior therapy that included interstitial        brachytherapy, stereotactic radiosurgery, or Gliadel wafers must        have confirmation of true progressive disease rather than        radiation necrosis based upon PET scanning, MR spectroscopy or        surgical documentation of disease.    -   A subset of 15 patients will be enrolled prior to a planned,        indicated surgical resection. Patients can be enrolled        pre-operatively only if they are surgical candidates, do not        have evidence of an acute intracranial hemorrhage and are able        to start protocol treatment in a window of 7 days before        surgery.    -   Male and female patients with reproductive potential must use an        approved contraceptive method, if appropriate (for example,        intrauterine device [IUD], birth control pills, or barrier        device) during and for 3 months after discontinuation of study        treatment. Women of childbearing potential must have a negative        beta-HCG pregnancy test documented within 14 days prior to        registration.    -   Blocks or slides of tumor tissue from a previous surgery must be        available to do IHC Rb staining. Patients with negative tumors        (Rb negative) will be excluded from the study.

Exclusion Criteria:

-   -   Patients must not have any significant medical illnesses that in        the investigator's opinion cannot be adequately controlled with        appropriate therapy or would compromise the patient's ability to        tolerate this therapy.    -   Patients with a history of any other cancer (except non-melanoma        skin cancer or carcinoma in-situ of the cervix), unless in        complete remission and off of all therapy for that disease for a        minimum of 3 years are ineligible.    -   Patients must not have an active infection or serious        intercurrent medical illness. Patients with a history of acute        intracranial hemorrhage will also be excluded.    -   Patients must not be pregnant/breast feeding and must agree to        practice adequate contraception.    -   Patients must not have any disease that will obscure toxicity or        dangerously alter drug metabolism.    -   Because of the potential for drug interactions, patients on        enzyme-inducing anti-epileptic drugs or other drugs that cause        CYP3A enzyme induction or inhibition will not be eligible unless        they are off therapy for at least 14 days    -   Patients with congenital or other reasons for prolongation of        the QT interval on EKG will be excluded.

Study Design:

A total of 30 patients with recurrent Glioblastoma or Gliosarcoma willbe treated with a compound of Formula (I), (II), (IIA), (IIB), (IIC),(IID), (III), (IV), (V) or (VI) at a dose of 125 mg daily for 21consecutive days followed by a 7 day break off therapy (cycle length is28 days). Of these 30 patients, 15 will receive drug for 7 days prior toan indicated, intended surgical resection for progression, and will thenresume drug at the same dose after recovery from surgery. Treatment willbe repeated every 28 days, and in the absence of disease progressionpatients may receive treatment for 12 cycles. At that time patients willbe given the option to continue on study past 12 cycles, up to a maximumof 24 cycles.

Following registration, available blocks or slides from a previoussurgery must be submitted for diagnosis review (confirmation ofGlioblastoma multiforme or Gliosarcoma) and Rb status determination.Only patients with Rb positive tumors can be treated, and Rb tumorstatus must be known prior to any treatment. Additional tissue fromprevious surgeries will also be obtained to evaluate molecularabnormalities in the tumor. These studies will be done retrospectivelyand are not required to be performed prior to registration.

Monitoring will include a clinical and neurological exam before thebeginning of each cycle (every 4 weeks). Complete blood counts withdifferential will be examined on days 1 and 15 of each cycle. Liver andrenal function will be performed every 4 weeks. Toxicity and dosemodifications will be based on the NCI CTCAE Version 4. Disease statuswill be assessed clinically each cycle (every 4 weeks) andradiographically after each second cycle (every 8 weeks).

Primary Outcome Measures:

-   -   Efficacy as determined by progression free survival [Time Frame:        1-2 years] [Designated as safety issue: No]    -   Determine the efficacy of a compound of Formula (I), (II),        (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI) in patients        with recurrent glioblastoma multiforme or gliosarcoma who are Rb        positive, as measured by progression free survival at 6 months.        A total of 30 patients will be treated; 15 who will undergo a        planned, intended surgical resection will receive drug for 7        days prior to surgery, followed by drug after recovery from        surgery, and 15 patients who receive drug without a planned        surgical procedure

Secondary Outcome Measures:

-   -   Number of Participants with Adverse Events as a Measure of        Safety and Tolerability [Time Frame: 1-2 years] [Designated as        safety issue: Yes]

Example 285: Phase II Clinical Trial of the Safety and Efficacy ofCompounds of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV),(V) or (VI) in Adults with Recurrent or Refractory Medulloblastoma

The purpose of this phase II trial is to how well a compound of Formula(I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI) works intreating adult patients with recurrent or refractory medulloblastoma.

Patients: Eligible subjects will be men and women 22 years and older.

Criteria:

Inclusion Criteria:

-   -   Patients with a histologically confirmed diagnosis of        medulloblastoma (including posterior fossa PNET) that is        recurrent, progressive, or refractory to standard therapy and        for which there is no known curative therapy are eligible; there        must be evidence of residual measurable disease or lesion in        pre-study MRI as described in section; patients with spinal        disease that is measurable will be eligible    -   The diagnosis should be confirmed at the treating institution        and tissue (either from the diagnosis or relapse or preferably        from both time points) must be available for biological studies    -   Patients with neurological deficits should have deficits that        are stable for a minimum of 1 week prior to registration; this        is to be documented in the database    -   Eastern Cooperative Oncology Group (ECOG) performance status 0-2    -   No other myelosuppressive chemotherapy or immunotherapy within 4        weeks prior to study entry (6 weeks if prior nitrosourea)    -   Decadron dose should also be stable or decreasing for at least 1        week (7 days) prior to starting therapy    -   Radiation therapy (XRT)>=3 months prior to study entry for        craniospinal irradiation (>=23 Gy); >=8 weeks for local        irradiation to primary tumor; >=2 weeks prior to study entry for        focal irradiation for symptomatic metastatic sites    -   Off all colony stimulating factors >=1 week prior to study entry        (GCSF, GM CSF, erythropoietin)    -   Absolute neutrophil count (ANC) >=1000/μL    -   Platelet count >=50,000/uL (transfusion independent)    -   Hemoglobin >=8.0 gm/dL (may receive RBC transfusions)    -   Creatinine clearance or radio-isotope GFR >=70 ml/min/1.73 m2 or    -   A serum creatinine=<2.0 mg/dL    -   Total bilirubin=<1.5× upper limit of normal (ULN) for age    -   Serum glutamic pyruvic transaminase (SGPT) (alanine        aminotransferase [ALT])=<2.5×institutional ULN    -   Serum glutamic-oxalacetic transaminase (SGOT) (aspartate        aminotransferase [AST])=<2.5 times institutional ULN    -   Serum albumin >=2.5 g/dL    -   Patient must have recovered from the significant acute        toxicities of all prior therapy before entering this study and        meet all other eligibility criteria    -   Pregnancy should be avoided for 12 months after the last dose        for females of child-bearing potential; female patients of        childbearing potential must not be pregnant or breast-feeding;        female patients of childbearing potential must have a negative        serum or urine pregnancy test within 24 hours prior to beginning        treatment    -   Women of childbearing potential are required to use 2 forms of        acceptable contraception, including one barrier method during        participation in the study and for the 12 months following the        last dose; for medical or personal reasons, 100% commitment to        abstinence is considered an acceptable form of birth control.        All patients should receive contraceptive counseling either by        the investigator, or by an OB/gynecologist or other physician        who is qualified in this area of expertise    -   Signed informed consent according to institutional guidelines        must be obtained

Exclusion Criteria:

-   -   Patients with any clinically significant unrelated systemic        illness (serious infections or significant cardiac, pulmonary,        hepatic or other organ dysfunction), that would compromise the        patient's ability to tolerate protocol therapy or would likely        interfere with the study procedures or results    -   Patients receiving any other anticancer or investigational drug        therapy    -   Patients with inability to return for follow-up visits or obtain        follow-up studies required to assess toxicity to therapy    -   Life expectancy <12 weeks as determined by treating physician    -   Inability to swallow capsules    -   Malabsorption syndrome or other condition that would interfere        with enteral absorption    -   History of congestive heart failure    -   History of ventricular arrhythmia requiring medication    -   Uncontrolled hypocalcemia, hypomagnesemia, hyponatremia or        hypokalemia defined as less than the lower limit of normal for        the institution despite adequate electrolyte supplementation    -   Congenital long QT syndrome

Study Design:

Patients receive a compound of Formula (I), (II), (IIA), (IIB), (IIC),(IID), (III), (IV), (V) or (VI) PO once daily on days 1-28. Treatmentrepeats every 28 days for up to 26 courses in the absence of diseaseprogression or unacceptable toxicity.

Primary Outcomes:

-   -   Objective response rates (PR and CR) graded using RECIST        criteria [Time Frame: Up to 12 months] [Designated as safety        issue: No]    -   Ninety-five percent confidence interval estimates of the true,        unknown objective response rate will be constructed for each of        the three strata. The proportions of patients with confirmed        complete responses, partial responses and stable disease will be        reported descriptively for each of the three strata. Cumulative        incidence functions of time to objective response will also be        provided.

Secondary Outcomes:

-   -   Duration of sustained objective response [Time Frame: From the        initial scan documenting complete or partial response that was        subsequently confirmed until the earlier of documented        progression or death on study, assessed up to 12 months]        [Designated as safety issue: No]    -   Progression-free survival [Time Frame: From the date of initial        treatment with a compound of Formula (I), (II), (IIA), (IIB),        (IIC), (IID), (III), (IV), (V) or (VI) until the earliest of        progression or death on study, assessed up to 12 months]        [Designated as safety issue: No]    -   Medical costs during the first 6 months after transplantation    -   Patient and graft survival

Example 286: Phase I/II Clinical Trial of the Safety, Tolerability, andAnti-Tumor Efficacy of Compounds of Formula (I), (II), (IIA), (IIB),(IIC), (IID), (III), (IV), (V) or (VI) in the Treatment of RecurrentMalignant Astrocytomas

This is a single-center, open-label, non-randomized, Phase I/IIa studyto investigate the safety, tolerability, and antitumor efficacy of acompound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV),(V) or (VI) in patients with recurrent malignant astrocytomas(glioblastoma, gliosarcoma, anaplastic astrocytoma, anaplasticoligodendroglioma, anaplastic oligoastrocytoma, and anaplasticependymoma). Patients will be treated for up to 5 cycles. A treatmentcycle is defined as 28 days+7 days rest (28+7 days during cycle 1 to 4,and 28 days during cycle 5). The following cycle will not be starteduntil the treatment continuation criteria are fulfilled. Concomitantsupportive therapies will be allowed.

Patients: Eligible subjects will be men and women ages 18 and older

Criteria:

Inclusion Criteria:

-   -   Be informed of the nature of the study and have provided written        informed consent    -   At least 18 years of age    -   ECOG performance of 0, 1, or 2, or KPS (Karnofsky performance        status) ≥60.    -   Pathological verification of a WHO grade 4 astrocytoma        (glioblastoma or gliosarcoma), or WHO Grade 3 anaplastic        astrocytoma, anaplastic oligodendroglioma, anaplastic        oligoastrocytoma, or anaplastic ependymoma.    -   Documented recurrent glioblastoma, gliosarcoma, anaplastic        astrocytoma, anaplastic oligodendroglioma, anaplastic        oligoastrocytoma, or anaplastic ependymoma after at least one        failed treatment of chemotherapy and radiation    -   Expected survival of at least 3 months    -   At least 2-weeks from cytoreductive surgery, if performed,        4-weeks from bevacizumab or other chemotherapy (6-weeks if prior        chemotherapy was nitrosourea) and 12-weeks from completion of        radiotherapy.    -   Ability to undergo MRI scanning without and with imaging dye on        a periodic basis as defined in the protocol    -   At least seven (7) days off of medications with induce CYP2C9        and CYP3A4 before administration of the first dose of a compound        of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III),        (IV), (V) or (VI)    -   Preserved major organ functions, i.e: Blood leukocyte count        ≥3.0×109/L Blood absolute neutrophil count ≥1.5×109/L Blood        platelet count ≥100×109/L Blood hemoglobin ≥100 g/L        (transfusions are allowed) Plasma total bilirubin level ≤1.5        times the upper institutional limit (ULN) of the ∥normal∥ (i.e.        reference) range Plasma AST (aspartate aminotransferase) or ALT        ≤2.5 times upper institutional limit (ULN) of the ∥normal∥ range        Plasma creatinine ≤1.5 times upper institutional limit (ULN) of        the ∥normal∥ range 12-lead ECG with normal tracings; or changes        that are not clinically significant and do not require medical        intervention, and QTc <500 ms At least seven (7) days off of        medications which inhibit or induce CYP2C9 or CYP3A4 before        first study treatment day.

Exclusion Criteria:

-   -   Ongoing infection or other major recent or ongoing disease that,        according to the Investigator, poses an unacceptable risk to the        patient    -   Grade 3 or higher constipation within the past 28 days or grade        2 constipation within the past 14 days before randomization.        (Patients with grade 2 constipation within the past 14 days        could be re-screened if constipation decreases to ≤grade 1 with        optimal management of constipation.)    -   Coexisting uncontrolled medical condition, including, but not        limited to, active cardiac disease and significant dementia    -   Hepatitis B or Hepatitis C, or HIV infection requiring        anti-retroviral therapy    -   Active malignancy other than basal cell skin cancer    -   Other active malignancy during the previous 3 years    -   Major surgical procedure within 4 weeks    -   Prior stereotactic or gamma knife radiosurgery or proton        radiation, unless unequivocal progression by functional        neuro-imaging (PET, dynamic MRI, MRS, SPECT) or by re-operation        with documented histologic confirmation of recurrence.    -   Prior anti-tumor therapy, as follows: at least 12-weeks from        radiation therapy; at least 4-weeks from prior treatment with        temozolomide or bevacizumab, 6-weeks from BCNU or CCNU.    -   Women of child bearing potential (WOCBP) who do not consent to        using acceptable methods of birth control (oral contraceptives,        IUD). For purposes of this study, WOCBP include any female who        has experienced menarche, who has not undergone tubal ligation,        and who is not postmenopausal. Post menopause is defined as:        amenorrhea ≥12 consecutive months without another cause.    -   Medically uncontrolled Type 1 or Type 2 diabetes mellitus    -   Pregnancy or lactation    -   Current participation in any other investigational clinical        trial within 4-weeks.    -   Eastern Cooperative Oncology Group (ECOG) performance status >2        after optimization of medications (See Appendix 4) or KPS <60    -   Anticipated Life expectancy less than 3 months    -   Contraindications to the investigational product or known or        suspected hypersensitivity    -   Patients who must take concomitant medications which induce or        are potent inhibitors of CYP2C9 or sensitive substrates of        CYP3A4 with narrow therapeutic range may not participate    -   Lack of suitability for participation in the trial, for any        reason, as judged by the Investigator

Study Design:

The trial will be divided in two phases. In the first phase, 10-20patients will be enrolled and treated with 300-520 mg BID of a compoundof Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or(VI) for 28 days. The primary endpoint of the first phase is todetermine the recommended Phase 2 dose (RP2D) of the compound of Formula(I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI) inpatients with recurrent or progressive glioblastoma and to assess thesafety and toxicity of the compound of Formula (I), (II), (IIA), (IIB),(IIC), (IID), (III), (IV), (V) or (VI) in this patient population. Thestudy has a 3+3 design and the first cohort will be treated with 400 mga compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III),(IV), (V) or (VI) BID for 28 days repeated in up to 5 cycles. Ifdose-limiting toxicity (DLT) such as neutropenia occurs, dosing will beinterrupted and the individual patient will, following normalization, berestarted on the same or a lower dose level according to standardizedprocedure. If two or three of the first 3 patients on a specific doselevel experience a DLT during the first 28 days of treatment with thecompound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV),(V) or (VI), the following patients will be treated with a lower doselevel. If one DLT occurs during the first 28 days of dosing in the first3 three patients another 3 patients will be treated with the same doselevel. If 2 of the 6 patients display DLT, the next patients will betreated with a lower dose level. The highest dose level without DLT orwith maximally one DLT out of 6 patients will be the RPTD. Allassessments with respect to dose adjustments for subsequent cohorts willbe done during the first 28 days of treatment. Non-progressing patientsmay be treated for a total of five 28-day cycles (24 weeks).

In the second phase, 12 patients will be enrolled and treated with theidentified RP2D of the compound of Formula (I), (II), (IIA), (IIB),(IIC), (IID), (III), (IV), (V) or (VI) for 28 days repeated in fivecycles. The primary endpoints of phase II is to assess the proportion ofpatients who are progression-free at 24 weeks and to assess safety,tolerability, and adverse event profile of the compound of Formula (I),(II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI).

Primary Outcomes:

-   -   Phase I—Determine recommended Phase II dose. [Time Frame: 8        months] [Designated as safety issue: Yes]    -   Phase II—Determine Antitumor effect [Time Frame: 4 months]        [Designated as safety issue: Yes]    -   Phase I—Number of Participants with Adverse Events as a Measure        of Safety and Tolerability [Time Frame: 6 months] [Designated as        safety issue: Yes]        -   physical/neurological examinations (pathological findings            and quality and quantity)        -   adverse events (quality and quantity per dose level)        -   vital signs, ECG, laboratory parameters (pathological            findings as quality and quantity, for laboratory parameters,            descriptive statistics)

Secondary Outcomes:

-   -   Renal Phase I—Maximum Tolerated Dose (MTD) [Time Frame: 8        months] [Designated as safety issue: Yes]    -   To identify the MTD of a compound of Formula (I), (II), (IIA),        (IIB), (IIC), (IID), (III), (IV), (V) or (VI).    -   Phase I—Molecular markers of optimum response [Time Frame: 8        months] [Designated as safety issue: Yes]    -   To assess potential molecular markers that might predict optimum        response sub-population groups    -   Phase I—Molecular Markers of IGF (insulin like growth factor)-1R        pathway [Time Frame: 8 months] [Designated as safety issue: Yes]    -   To evaluate surrogate molecular markers of IGF-1R pathway        activation/inhibition after treatment with the compound of        Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V)        or (VI) in patients with malignant astrocytomas    -   Phase II—Time-To-Progression (TTP) and Overall Survival (OS)        [Time Frame: 4 months] [Designated as safety issue: Yes]    -   To determine time-to-progression (TTP) and overall survival (OS)        of patients treated with the compound of Formula (I), (II),        (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI)    -   Phase II—Overall Response Rate [Time Frame: 4 months]        [Designated as safety issue: Yes]    -   To assess overall response rate (ORR) in recurrent malignant        astrocytomas after treatment with the compound of Formula (I),        (II), (IIA), (IIB), (IIC), (ID), (III), (IV), (V) or (VI)    -   Phase II—Imaging Evidence of Response. [Time Frame: 4 months]        [Designated as safety issue: Yes]    -   To identify surrogate imaging evidence of response on MRI        (magnetic resonance imaging) sequences by RANO criteria (with        additional special attention to T2-FLAIR, DWI        (diffusion-weighted imaging), perfusion MRI and multi-voxel MRS        (magnetic resonance spectroscopy) sequences).

Example 287: Pharmaceutical Compositions Example 287A: ParenteralComposition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a compound of Formula (I), (II),(IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI) is dissolved inDMSO and then mixed with 10 mL of 0.9% sterile saline. The mixture isincorporated into a dosage unit form suitable for administration byinjection.

In another embodiment, the following ingredients are mixed to form aninjectable formulation:

Ingredient Amount Compound of Formula (I), (II), (IIA), (IIB), (IIC),1.2 g (IID), (III), (IV), (V) or (VI) sodium acetate buffer solution(0.4M) 2.0 mL HCl (1N) or NaOH (1M) q.s. to suitable pH water(distilled, sterile) q.s. to 20 mL

All of the above ingredients, except water, are combined and stirred andif necessary, with slight heating if necessary. A sufficient quantity ofwater is then added.

Example 287B: Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV),(V) or (VI) is mixed with 750 mg of starch. The mixture is incorporatedinto an oral dosage unit, such as a hard gelatin capsule, which issuitable for oral administration.

In another embodiment, the following ingredients are mixed intimatelyand pressed into single scored tablets.

Ingredient Quantity per tablet, mg compound of Formula (I), (II), (IIA),(IIB), (IIC), 200 (IID), (III), (IV), (V) or (VI) Cornstarch 50croscarmellose sodium 25 Lactose 120 magnesium stearate 5

In yet another embodiment, the following ingredients are mixedintimately and loaded into a hard-shell gelatin capsule.

Ingredient Quantity per tablet, mg compound of Formula (I), (II), (IIA),(IIB), (IIC), 200 (IID), (III), (IV), (V) or (VI) lactose, spray-dried148 magnesium stearate 2

In yet another embodiment, the following ingredients are mixed to form asolution/suspension for oral administration:

Ingredient Amount Compound of Formula (I), (II), (IIA), (IIB), (IIC), 1g (IID), (III), (IV), (V) or (VI) 0.1 g Anhydrous Sodium CarbonateEthanol (200 proof), USP 10 mL Purified Water, USP 90 mL Aspartame 0.003g

Example 287C: Sublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as ahard lozenge, mix 100 mg of a compound of Formula (I), (II), (IIA),(IIB), (IIC), (IID), (III), (IV), (V) or (VI) with 420 mg of powderedsugar mixed with 1.6 mL of light corn syrup, 2.4 mL distilled water, and0.42 mL mint extract. The mixture is gently blended and poured into amold to form a lozenge suitable for buccal administration.

Example 287D: Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof a compound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III),(IV), (V) or (VI) is mixed with 50 mg of anhydrous citric acid and 100mL of 0.9% sodium chloride solution. The mixture is incorporated into aninhalation delivery unit, such as a nebulizer, which is suitable forinhalation administration.

Example 287E: Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of acompound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV),(V) or (VI) is mixed with 2.5 g of methylcellulose (1500 mPa), 100 mg ofmethylparaben, 5 g of glycerin and 100 mL of purified water. Theresulting gel mixture is then incorporated into rectal delivery units,such as syringes, which are suitable for rectal administration.

Example 287F: Suppository Formulation

A suppository of total weight 2.5 g is prepared by mixing a compound ofFormula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV), (V) or (VI)with Witepsol™ H-15 (triglycerides of saturated vegetable fatty acid;Riches-Nelson, Inc., New York), and has the following composition:

Quantity per Ingredient suppository, mg compound of Formula (I), (II),(IIA), (IIB), (IIC), 500 (IID), (III), (IV), (V) or (VI) Witepsol ® H-15balance

Example 287G: Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV),(V) or (VI) is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL ofpropylene glycol, 10 mL of isopropyl myristate and 100 mL of purifiedalcohol USP. The resulting gel mixture is then incorporated intocontainers, such as tubes, which are suitable for topicaladministration.

Example 287H: Ophthalmic Solution Composition

To prepare a pharmaceutical ophthalmic solution composition, 100 mg of acompound of Formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (IV),(V) or (VI) is mixed with 0.9 g of NaCl in 100 mL of purified water andfiltered using a 0.2 micron filter. The resulting isotonic solution isthen incorporated into ophthalmic delivery units, such as eye dropcontainers, which are suitable for ophthalmic administration.

The examples and embodiments described herein are for illustrativepurposes only and in some embodiments, various modifications or changesare to be included within the purview of disclosure and scope of theappended claims.

What is claimed is:
 1. A compound having the structure of Formula (I):

wherein: A is a bond, O, or N(R₁₀); X, Y, and Z are each independentlyN, or C(R₇) wherein at least one of X, Y, and Z are N; each R₁ isindependently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃,—SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉, —C(═O)R₉,—CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl; or two R₁ are taken together to form asubstituted or unsubstituted heterocyclic ring or a substituted orunsubstituted carbocyclic ring; R₂ and R₃ are each independently H, —CN,C₁-C₄alkyl, C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ aretaken together to form a 5- or 6-membered heterocyclic ring; R₅ ishalogen, —CN, —OH, —CF₃, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆alkoxy, substituted or unsubstitutedC₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl,substituted or unsubstituted C₃-C₈cycloalkyl, substituted orunsubstituted C₆-C₁₀aryl, or substituted or unsubstitutedC₂-C₇heteroaryl; R₆ is substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₃-C₈cycloalkyl,substituted or unsubstituted C₂-C₇heteroaryl, —(C(R₁₄)(R₁₅))_(m)R₂₁,—(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂), or

R₁₁ and R₁₂ are each independently H, or substituted or unsubstitutedC₁-C₆alkyl; or R₁₁ and R₁₂ are taken together to form a 5-, 6-, 7-, or8-membered heterocyclic ring; J is C(H), or N; R₁₃ is H, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₃-C₈cycloalkyl,substituted or unsubstituted —C₁-C₄alkylC₆-C₁₀aryl, or substituted orunsubstituted —C₁-C₄alkylC₂-C₇heteroaryl; each R₇ is independently H,halogen, —CN, —OH, —CF₃, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆alkoxy, substituted or unsubstitutedC₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl,substituted or unsubstituted C₃-C₈cycloalkyl, substituted orunsubstituted C₆-C₁₀aryl, or substituted or unsubstitutedC₂-C₇heteroaryl; each R₁₄ and R₁₅ are each independently H, orsubstituted or unsubstituted C₁-C₆alkyl; or R₁₄ and R₁₅ are takentogether to form a 4-, 5-, 6-membered cycloalkyl ring; R₂₁ is halogen,—CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃, —SR₂₂, —N(R₂₂)S(═O)₂R₂₃,—S(═O)₂N(R₂₂)₂, —S(═O)R₂₃, —S(═O)₂R₂₃, —C(═O)R₂₃, —CO₂R₂₂,—C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substituted or unsubstitutedC₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl, substitutedor unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl; each R₂₂ is independently H, orsubstituted or unsubstituted C₁-C₆alkyl; R₂₃ is substituted orunsubstituted C₁-C₆alkyl; each R₈ is independently H, or substituted orunsubstituted C₁-C₆alkyl; R₉ is substituted or unsubstituted C₁-C₆alkyl;R₁₀ is H or unsubstituted C₁-C₄alkyl; m is 2-6; n is 0-5; p is 1-3; q is1-3; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.2. The compound of claim 1, wherein R₂ and R₃ are each independently H,—CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl.
 3. Thecompound of claim 2, wherein R₂ and R₃ are each H.
 4. The compound ofclaim 1, wherein R₂ and R₃ are taken together to form a 5- or 6-memberedheterocyclic ring.
 5. The compound of claim 4, wherein R₂ and R₃ aretaken together to form a 5-membered heterocyclic ring.
 6. The compoundof any one of claims 1-5, wherein R₆ is substituted or unsubstitutedC₂-C₇heteroaryl.
 7. The compound of claim 6, wherein R₆ is substitutedor unsubstituted pyridyl.
 8. The compound of claim 7, wherein R₆ isunsubstituted pyridyl.
 9. The compound of any one of claims 1-5, whereinR₆ is


10. The compound of claim 9, wherein R₁₃ is H.
 11. The compound of claim9, wherein R₁₃ is substituted or unsubstituted C₁-C₆ alkyl.
 12. Thecompound of claim 11, wherein R₁₃ is —CH₃.
 13. The compound of claim 11,wherein R₁₃ is —CH₂CH₃.
 14. The compound of any one of claims 9-13,wherein J is C(H).
 15. The compound of claim 14, wherein p is 2 and qis
 1. 16. The compound of claim 14, wherein p is 3 and q is
 1. 17. Thecompound of claim 14, wherein p is 2 and q is
 2. 18. The compound of anyone of claims 9-13, wherein J is N.
 19. The compound of claim 18,wherein p is 2 and q is
 2. 20. The compound of any one of claims 1-5,wherein R₆ is substituted or unsubstituted C₂-C₇heterocycloalkyl. 21.The compound of claim 20, wherein R₆ is substituted or unsubstitutedmorpholinyl.
 22. The compound of claim 20, wherein R₆ is substituted orunsubstituted piperidinyl.
 23. The compound of any one of claims 1-5,wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₂₁.
 24. The compound of claim 23,wherein R₂₁ is —OH.
 25. The compound of any one of claims 1-5, whereinR₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂).
 26. The compound of claim 25,wherein R₁₁ and R₁₂ are each CH₃.
 27. The compound of any one of claims23-26, wherein R₁₄ and R₁₅ are each H.
 28. The compound of any one ofclaims 23-27, wherein m is
 2. 29. The compound of any one of claims23-27, wherein m is
 3. 30. The compound of any one of claims 1-29,wherein A is N(R₁₀).
 31. The compound of claim 30, wherein R₁₀ is H orCH₃.
 32. The compound of any one of claims 1-29, wherein A is O.
 33. Thecompound of any one of claims 1-29, wherein A is a bond.
 34. Thecompound of any one of claims 1-33, wherein R₅ is substituted orunsubstituted C₁-C₆alkyl.
 35. The compound of claim 34, wherein R₅ isCH₃.
 36. The compound of claim 34, wherein R₅ is CH₂CH₃.
 37. Thecompound of any one of claims 1-36, wherein n is
 2. 38. The compound ofany one of claims 1-36, wherein n is
 1. 39. The compound of any one ofclaims 1-36, wherein n is
 0. 40. The compound of any one of claims 1-38,wherein each R₁ is independently halogen, —CN, —NO₂, —OH, —CF₃,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl, substitutedor unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl.
 41. The compound of claim 40, whereineach R₁ is independently halogen, —CN, —OH, —CF₃, substituted orunsubstituted C₁-C₆alkyl, or substituted or unsubstituted C₁-C₆alkoxy.42. The compound of any one of claims 1-37, wherein two R₁ are takentogether to form a substituted or unsubstituted heterocyclic ring or asubstituted or unsubstituted carbocyclic ring.
 43. The compound of anyone of claims 1-42, wherein X is C(R₇); Y is N; and Z is N.
 44. Thecompound of any one of claims 1-42, wherein X is C(R₇); Y is C(R₇); andZ is N.
 45. The compound of any one of claims 1-42, wherein X is C(R₇);Y is N; and Z is C(R₇).
 46. The compound of any one of claims 1-42,wherein X is C(R₇); Y is C(R₇); and Z is C(R₇).
 47. The compound of anyone of claims 1-46, wherein R₇ is H.
 48. A compound having the structureof Formula (II):

wherein: each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃,—OCH₂F, —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,—S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl, substitutedor unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl; or two R₁ are taken together to form asubstituted or unsubstituted heterocyclic ring or a substituted orunsubstituted carbocyclic ring; R₂ and R₃ are each independently H, —CN,C₁-C₄alkyl, C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ aretaken together to form a 5- or 6-membered heterocyclic ring; R₅ ishalogen, —CN, —OH, —CF₃, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆alkoxy, substituted or unsubstitutedC₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl,substituted or unsubstituted C₃-C₈cycloalkyl, substituted orunsubstituted C₆-C₁₀aryl, or substituted or unsubstitutedC₂-C₇heteroaryl; R₆ is substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₃-C₈cycloalkyl,substituted or unsubstituted C₂-C₇heteroaryl, —(C(R₁₄)(R₁₅))_(m)R₂₁, or

J is C(H); R₁₃ is H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted orunsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted—C₁-C₄alkylC₆-C₁₀aryl, or substituted or unsubstituted—C₁-C₄alkylC₂-C₇heteroaryl; each R₁₄ and R₁₅ are each independently H,or substituted or unsubstituted C₁-C₆alkyl; or R₁₄ and R₁₅ are takentogether to form a 4-, 5-, 6-membered cycloalkyl ring; R₂₁ is halogen,—CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃, —SR₂₂, —N(R₂₂)S(═O)₂R₂₃,—S(═O)₂N(R₂₂)₂, —S(═O)R₂₃, —S(═O)₂R₂₃, —C(═O)R₂₃, —CO₂R₂₂,—C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substituted or unsubstitutedC₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl, substitutedor unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted C₆-C₁₀aryl, or substituted or unsubstitutedC₂-C₇heteroaryl; each R₂₂ is independently H, or substituted orunsubstituted C₁-C₆alkyl; R₂₃ is substituted or unsubstitutedC₁-C₆alkyl; each R₈ is independently H, or substituted or unsubstitutedC₁-C₆alkyl; R₉ is substituted or unsubstituted C₁-C₆ alkyl; R₁₀ is H orunsubstituted C₁-C₄alkyl; m is 2-6; n is 0-5; p is 1-3; q is 1-3; or apharmaceutically acceptable salt, solvate, or prodrug thereof.
 49. Thecompound of claim 48, wherein R₂ and R₃ are each independently H, —CN,C₁-C₄alkyl, C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl.
 50. The compoundof claim 49, wherein R₂ and R₃ are each H.
 51. The compound of claim 48,wherein R₂ and R₃ are taken together to form a 5- or 6-memberedheterocyclic ring.
 52. The compound of claim 51, wherein R₂ and R₃ aretaken together to form a 5-membered heterocyclic ring.
 53. The compoundof any one of claims 48-52, wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₂₁.
 54. Thecompound of any one of claims 48-53, wherein R₂₁ is —OH,—N(R₂₂)S(═O)₂R₂₃, —CO₂R₂₂, —C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substitutedor unsubstituted C₁-C₆alkoxy, or substituted or unsubstitutedC₂-C₇heteroaryl.
 55. The compound of claim 54, wherein R₂₁ is —OH. 56.The compound of claim 54, wherein R₂₁ is —N(R₂₂)S(═O)₂R₂₃.
 57. Thecompound of claim 54, wherein R₂₁ is —N(R₂₂)C(═O)R₂₃.
 58. The compoundof claim 54, wherein R₂₁ is substituted or unsubstituted C₁-C₆alkoxy.59. The compound of claim 54, wherein R₂₁ is substituted orunsubstituted C₂-C₇heteroaryl.
 60. The compound of any one of claims48-59, wherein each R₂₂ is independently H or unsubstituted C₁-C₆alkyl;and R₂₃ is unsubstituted C₁-C₆alkyl.
 61. The compound of any one ofclaims 48-60, wherein R₁₄ and R₁₅ are each independently H, orsubstituted or unsubstituted C₁-C₆alkyl.
 62. The compound of any one ofclaims 48-60, wherein R₁₄ and R₁₅ are each H.
 63. The compound of anyone of claims 48-62, wherein m is
 2. 64. The compound of any one ofclaims 48-62, wherein m is
 3. 65. The compound of any one of claims48-52, wherein R₆ is substituted or unsubstituted C₂-C₇heteroaryl. 66.The compound of claim 65, wherein R₆ is substituted or unsubstitutedpyridyl.
 67. The compound of any one of claims 48-52, wherein R₆ issubstituted or unsubstituted C₂-C₇heterocycloalkyl.
 68. The compound ofclaim 67, wherein R₆ is substituted or unsubstituted morpholinyl. 69.The compound of claim 67, wherein R₆ is substituted or unsubstitutedpiperidinyl.
 70. The compound of any one of claims 48-69, wherein R₁₀ isH or CH₃.
 71. A compound having the structure of Formula (IIA):

wherein: each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃,—OCH₂F, —OCF₂H, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,—S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl, substitutedor unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl; or two R₁ are taken together to form asubstituted or unsubstituted heterocyclic ring or a substituted orunsubstituted carbocyclic ring; R₂ and R₃ are each independently H, —CN,C₁-C₄alkyl, C₃-C₆cycloalkyl, or C₂-C₇heterocycloalkyl; or R₂ and R₃ aretaken together to form a 5- or 6-membered heterocyclic ring; R₄ is H,halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —SR₈, —N(R₈)S(═O)₂R₉,—S(═O)₂N(R₈)₂, —S(═O)R₉, —S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂,—C(═O)N(R₈)₂, —N(R₈)C(═O)R₉, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆alkoxy, substituted or unsubstitutedC₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl,substituted or unsubstituted C₃-C₈cycloalkyl, substituted orunsubstituted C₆-C₁₀aryl, or substituted or unsubstitutedC₂-C₇heteroaryl; or two R₁ are taken together to form a substituted orunsubstituted heterocyclic ring or a substituted or unsubstitutedcarbocyclic ring; wherein when n is 0, R₄ is not halogen; R₅ is halogen,—CN, —OH, —CF₃, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkoxy, substituted or unsubstitutedC₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl,substituted or unsubstituted C₃-C₈cycloalkyl, substituted orunsubstituted C₆-C₁₀aryl, or substituted or unsubstitutedC₂-C₇heteroaryl; R₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂); R₁₁ and R₁₂ areeach independently H, or substituted or unsubstituted C₁-C₆alkyl; or R₁₁and R₁₂ are taken together to form a 5-, 6-, 7-, or 8-memberedheterocyclic ring; R₁₃ is H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted orunsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted—C₁-C₄alkylC₆-C₁₀aryl, or substituted or unsubstituted—C₁-C₄alkylC₂-C₇heteroaryl; each R₁₄ and R₁₅ are each independently H,or substituted or unsubstituted C₁-C₆alkyl; or R₁₄ and R₁₅ are takentogether to form a 4-, 5-, 6-membered cycloalkyl ring; each R₈ isindependently H, or substituted or unsubstituted C₁-C₆alkyl; R₉ issubstituted or unsubstituted C₁-C₆alkyl; R₁₀ is H, or C₁-C₄alkyl; m is2-6; n is 0-4; or a pharmaceutically acceptable salt, solvate, orprodrug thereof.
 72. The compound of claim 71, wherein R₂ and R₃ areeach independently H, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, orC₂-C₇heterocycloalkyl.
 73. The compound of claim 72, wherein R₂ and R₃are each H.
 74. The compound of claim 71, wherein R₂ and R₃ are takentogether to form a 5- or 6-membered heterocyclic ring.
 75. The compoundof claim 74, wherein R₂ and R₃ are taken together to form a 5-memberedheterocyclic ring.
 76. The compound of any one of claims 71-75, whereinR₆ is —(C(R₁₄)(R₁₅))_(m)N(R₁₁)(R₁₂) and R₁₄ and R₁₅ are each H.
 77. Thecompound of claim 76, wherein R₁₁ and R₁₂ are each independently H, orsubstituted or unsubstituted C₁-C₆alkyl.
 78. The compound of claim 77,wherein R₁₁ and R₁₂ are each independently unsubstituted C₁-C₆alkyl. 79.The compound of claim 78, wherein R₁₁ and R₁₂ are each —CH₃.
 80. Thecompound of any one of claims 71-79, wherein m is
 2. 81. The compound ofany one of claims 71-79, wherein m is
 3. 82. The compound of any one ofclaims 71-81, wherein R₁₀ is H or CH₃.
 83. The compound of any one ofclaims 71-82, wherein n is
 0. 84. The compound of any one of claims71-82, wherein n is
 1. 85. A compound having the structure of Formula(VI):

wherein: each R₁ is independently halogen, —CN, —NO₂, —OH, —OCF₃,—OCH₂F, —OCF₂H, —CF₃, —SR₈, —N(R₈)S(═O)₂R₉, —S(═O)₂N(R₈)₂, —S(═O)R₉,—S(═O)₂R₉, —C(═O)R₉, —CO₂R₈, —N(R₈)₂, —C(═O)N(R₈)₂, —N(R₈)C(═O)R₉,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl, substitutedor unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstitutedC₃-C₈cycloalkyl, substituted or unsubstituted C₆-C₁₀aryl, or substitutedor unsubstituted C₂-C₇heteroaryl; or two R₁ are taken together to form asubstituted or unsubstituted heterocyclic ring or a substituted orunsubstituted carbocyclic ring; R₂ and R₃ are each independently H orC₁-C₄alkyl; or R₂ and R₃ are taken together to form a 5- or 6-memberedheterocyclic ring; R₅ is substituted or unsubstituted C₁-C₆alkyl; R₆ isunsubstituted C₁-C₄alkyl, substituted or unsubstitutedC₂-C₇heterocycloalkyl, substituted or unsubstituted C₃-C₈cycloalkyl,substituted or unsubstituted C₂-C₇heteroaryl, —(C(R₁₄)(R₁₅))_(m)R₂₁,

J is C(H); R₁₃ is H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted orunsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted—C₁-C₄alkylC₆-C₁₀aryl, or substituted or unsubstituted—C₁-C₄alkyC₂-C₇heteroaryl; each R₁₄ and R₁₅ are each independently H,halogen, or substituted or unsubstituted C₁-C₆alkyl; R₂₁ is halogen,—CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃, —SR₂₂, —N(R₂₂)S(═O)₂R₂₃,—S(═O)₂N(R₂₂)₂, —S(═O)R₂₃, —S(═O)₂R₂₃, —C(═O)R₂₃, —CO₂R₂₂,—C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substituted or unsubstitutedC₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl, substitutedor unsubstituted C₂-C₇heterocycloalkyl, or substituted or unsubstitutedC₂-C₇heteroaryl; each R₂₂ is independently H, or substituted orunsubstituted C₁-C₆alkyl; R₂₃ is substituted or unsubstitutedC₁-C₆alkyl; each R₈ is independently H, or substituted or unsubstitutedC₁-C₆alkyl; R₉ is substituted or unsubstituted C₁-C₆alkyl; R₁₀ is H; mis 2-6; n is 0-5; p is 1-3; q is 1-3; or a pharmaceutically acceptablesalt, solvate, or prodrug thereof.
 86. The compound of claim 85, whereinR₂ and R₃ are each independently H or C₁-C₄alkyl.
 87. The compound ofclaim 86, wherein R₂ and R₃ are each H.
 88. The compound of claim 85,wherein R₂ and R₃ are taken together to form a 5- or 6-memberedheterocyclic ring.
 89. The compound of claim 88, wherein R₂ and R₃ aretaken together to form a 5-membered heterocyclic ring.
 90. The compoundof any one of claims 85-89, wherein R₆ is —(C(R₁₄)(R₁₅))_(m)R₂₁.
 91. Thecompound of any one of claims 85-90, wherein each R₁₄ and R₁₅ are eachindependently H, halogen, or unsubstituted C₁-C₆alkyl.
 92. The compoundof any one of claims 85-90, wherein R₁₄ and R₁₅ are each H.
 93. Thecompound of any one of claims 85-92, wherein R₂₁ is —OH,—N(R₂₂)S(═O)₂R₂₃, —CO₂R₂₂, —C(═O)N(R₂₂)₂, —N(R₂₂)C(═O)R₂₃, substitutedor unsubstituted C₁-C₆alkoxy, or substituted or unsubstitutedC₂-C₇heteroaryl.
 94. The compound of claim 93, wherein R₂₁ is —OH. 95.The compound of claim 93, wherein R₂₁ is —N(R₂₂)S(═O)₂R₂₃.
 96. Thecompound of claim 93, wherein R₂₁ is —N(R₂₂)C(═O)R₂₃.
 97. The compoundof claim 93, wherein R₂₁ is substituted or unsubstituted C₁-C₆alkoxy.98. The compound of claim 93, wherein R₂₁ is substituted orunsubstituted C₂-C₇heteroaryl.
 99. The compound of any one of claims85-98, wherein each R₂₂ is independently H or unsubstituted C₁-C₆alkyl;and R₂₃ is unsubstituted C₁-C₆alkyl.
 100. The compound of any one ofclaims 85-99, wherein m is
 2. 101. The compound of any one of claims85-99, wherein m is
 3. 102. The compound of any one of claims 85-89,wherein R₆ is


103. The compound of any one of claims 85-89, wherein R₆ is


104. The compound of claim 102 or 103, wherein R₁₃ is H or unsubstitutedC₁-C₆alkyl,
 105. The compound of any one of claims 85-104, wherein eachR₁ is independently halogen, —OCF₃, —CF₃, unsubstituted C₁-C₆alkyl, orunsubstituted C₁-C₆alkoxy.
 106. The compound of any one of claims85-104, wherein each R₁ is independently halogen.
 107. The compound ofany one of claims 85-106, wherein n is
 1. 108. The compound of any oneof claims 85-106, wherein n is
 2. 109. The compound of any one of claims85-104, wherein n is
 0. 110. A compound having a structure selectedfrom:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 111.A pharmaceutical composition comprising a compound of any one of claims1-110, or a pharmaceutically acceptable salt, solvate, or prodrugthereof, and at least one pharmaceutically acceptable excipient.
 112. Amethod for treating a disease in a subject comprising administering tothe subject in need thereof a composition comprising a compound of anyone of claims 1-110, or a pharmaceutically acceptable salt, solvate, orprodrug thereof, wherein the disease is cancer or Down's Syndrome. 113.The method of claim 112, wherein the disease is cancer.
 114. The methodof claim 113, wherein the cancer is brain cancer, glioblastomamultiforme, medulloblastoma, astrocytomas, brain stem gliomas,meningiomas, oligodendrogliomas, melanoma, lung cancer, breast cancer,or leukemia.
 115. The method of claim 112, wherein the disease is Down'sSyndrome.
 116. A method for inhibiting the activity of Olig2 in a cellcomprising contacting the cell with a compound of any one of claims1-110, or a pharmaceutically acceptable salt, solvate, or prodrugthereof.